FINDING SOLUTIONS
THAT COULD CHANGE
THE WORLD



Southern Research Drug Discovery

The Drug Discovery Division conducts basic and translational research with a focus in oncology, infectious diseases and neuroscience. With a faculty and staff of approximately 75 scientists, we emphasize cutting-edge research on novel mechanisms and challenging targets with the goal of identifying new drugs for today’s most significant healthcare challenges.

In addition to our internal research efforts, the Division participates in many academic and industrial collaborations and research partnerships. And through the Alabama Drug Discovery Alliance, our work with investigators from the University of Alabama at Birmingham has resulted in a number of potential new drug therapies.

The Division is partially funded by multiple institutional and investigator grants from the National Institutes of Health and other federal institutions, including the Department of Defense. In addition, we have secured competitive funding from a range of private foundations including The Cystic Fibrosis Foundation, The Muscular Dystrophy Foundation, The Bright House Foundation, The Amyotrophic Lateral Sclerosis Association, and The Steven & Alexandra Cohen Foundation.



Drug Discovery Departments

High-Throughput Screening
Infectious Disease Drug Discovery
Chemistry Drug Discovery
Center for Neuromolecular Research

How To Work With Us

 

Southern Research’s Drug Discovery Division welcomes collaboration opportunities
with both academic and industrial research partners.

ADDA Discovery Pipeline

Through the Alabama Drug Discovery Alliance (ADDA), Southern Research collaborates closely with researchers at the University of Alabama at Birmingham (UAB) to leverage the strengths and capabilities of both institutions in addressing unmet medical needs. Established in 2008, the ADDA facilitates and expedites the discovery and development of new drug therapies.

Through internal and external funding sources, the ADDA advances promising discovery research originating in UAB and Southern Research labs through pre-clinical development. The alliance emphasizes research in the areas of oncology, infectious diseases, and CNS/neurological disorders, but also considers other programs in areas of unmet medical need.

Southern Research Discovery Pipeline

Therapy for Chronic Pseudomonas aeruginosa Infections

We are developing an engineered version of the filamentous Pf phage for the treatment of biofilm-related chronic P. aeruginosa infections. While highly resistant to antibiotics, P. aeruginosa biofilms are very accessible to Pf phage since Pf is normally found in biofilms. We are designing the phage to disrupt biofilms after infection. The engineered phage will destabilize the entire biofilm and induce its dispersion, making the P. aeruginosa susceptible to host immune defenses and lower-dose antibiotic treatment.

 

SRI-22138 for Pain

We have identified a series of opioid compounds with a greatly reduced side effect profile as compared to classic opioids such as morphine. SRI-22138 is the lead compound with strong agonism at the mu receptor subtype and strong antagonism at the delta receptor subtype. In vivo studies have shown that SRI-22138 has greatly reduced tolerance induction and abuse liability as compared to morphine.

 

PD1 Small Molecule Inhibitors for Oncology

Small molecule and peptide inhibitors of immune checkpoint systems offer several advantages over monoclonal antibodies, including lower cost and the potential for oral and topical uses. These advantages have the potential to increase the range of indications for these inhibitors beyond oncology. We have designed a series of peptides that inhibit PD1-PDL1 binding in a dose-dependent manner. Efforts are now underway to identify a peptide that is optimized for size, efficacy and stability.

We have also conducted a pilot high-throughput screen and identified several confirmed hits. Plans are underway to conduct a larger screen of 250,000 compounds.

Patents & Publications

DDS Patents Q3 2016

Filed

  • “Methods and Compositions for Inhibiting PD-1:PD-L1 Interaction”
  • “Benzimidazole Compounds, Use as Inhibitors of WNT Signaling Pathway in Cancers, and Methods for Preparation Thereof”
  • “Pyrrolopyrimidine Compounds, Use as Inhibitors of the Kinase LRRK2, and Methods for Preparation Thereof”
  • “Synergistic Effect of Gefitinib and MEK1 Inhibitors in Colon Cancer”
  • “Treatment of Hepatitis B Virus”

 

Published

  • “Antiviral Agents” (Norovirus Compounds); PCT – WO2016094361 6/16
  • “Heterocyclic Compounds as Biogenic Amine Transport Modulators”; US 20160159809 6/16; PCT – WO2016090296 6/16
  • “Novel Quinazolines as Biogenic Amine Transport Modulators”; US 20160159751 6/16; PCT – WO2016090299 6/16
  • “Small Molecules That Enhance the Activity of Oligonucleotides”; PCT – WO2016003816 1/16
  • “Inhibitors of Hepatocyte Growth Factor [HGF] and Macrophage Stimulating Protein Maturation”; PCT – WO2015184222 3/15
  • “Urea and Amide Derivatives of Aminoalkylpiperazines and Use Thereof” US 20150232435 4/14; PCT – WO2014059265 4/14
  • “Compounds, Compositions and Methods for the Treatment of Diseases Through inhibiting TGF- Activity”. US Pub # 20140336115; PCT – WO2014183018 11/14

 

Issued

  • “Substituted Pyridine and Pyrimidine Derivatives and their use in Treating Viral Infections”. #9,433,621
  • “Antiviral Agents”. #9,375,419
  • “Derivatives of Sulindac, Use Thereof and Preparation Thereof”. #9,365,528
  • “Compounds, Compositions and Methods for the Treatment of Diseases Through Inhibiting TGF-.beta. Activity”. #9,353,149
  • “Heterocycle-Fused Morphinans, Use Thereof and Preparation Thereof” #9,163,030
  • “Substituted Pyridine and Pyrimidine Derivatives and their use in Treating Viral Infections”. #8,697,694
2017 Publications

Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.

Everts, M., Cihlar, T., Bostwick, J. R. & Whitley, R. J. (2017).

Annu Rev Pharmacol Toxicol 57, 155-169.

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Differential Growth of Francisella tularensis, Which Alters Expression of Virulence Factors, Dominant Antigens, and Surface-Carbohydrate Synthases, Governs the Apparent Virulence of Ft SchuS4 to Immunized Animals.

Holland, K. M., Rosa, S. J., Kristjansdottir, K., Wolfgeher, D., Franz, B. J., Zarrella, T. M., Kumar, S., Sunagar, R., Singh, A., Bakshi, C. S., Namjoshi, P., Barry, E. M., Sellati, T. J., Kron, S. J., Gosselin, E. J., Reed, D. S. & Hazlett, K. R. O. (2017).

Front Microbiol 8, 1158.

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Role of Wnt Co-Receptor LRP6 in Triple Negative Breast Cancer Cell Migration and Invasion.

Ma, J., Lu, W., Chen, D., Xu, B. & Li, Y. (2017).

J Cell Biochem. 118, 2968-2976.

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Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit.

Oliva, C. R., Zhang, W., Langford, C., Suto, M. J. & Griguer, C. E. (2017).

Oncotarget 8, 37568-37583.

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Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment.

Owusu, B. Y., Galemmo, R., Janetka, J. & Klampfer, L. (2017).

Cancers (Basel) 9, 35.

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Modulation of STAT1-Driven Transcriptional Activity by Histone Deacetylases.

Owusu, B. Y. & Klampfer, L. (2017).

Methods Mol Biol 1510, 277-285.

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Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation.

Owusu, B. Y., Thomas, S., Venukadasula, P., Han, Z., Janetka, J. W., Galemmo, R. A., Jr. & Klampfer, L. (2017).

Oncotarget doi: 10.18632/oncotarget.18260

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Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia.

Singh, A., Rahman, T., Bartiss, R., Arabshahi, A., Prasain, J., Barnes, S., Musteata, F. M. & Sellati, T. J. (2017).

J Leukoc Biol 101, 531-542.

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Development of a radiosensitivity gene signature for patients with soft tissue sarcoma.

Tang, Z., Zeng, Q., Li, Y., Zhang, X., Ma, J., Suto, M. J., Xu, B. & Yi, N. (2017).

Oncotarget 8, 27428-27439.

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Dual-Modality Imaging of Prostate Cancer with a Fluorescent and Radiogallium-Labeled Gastrin-Releasing Peptide Receptor Antagonist.

Zhang, H., Desai, P., Koike, Y., Houghton, J., Carlin, S., Tandon, N., Touijer, K. & Weber, W. A. (2017).

J Nucl Med 58, 29-35.

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Pathway-Structured Predictive Model for Cancer Survival Prediction: A Two-Stage Approach.

Zhang, X., Li, Y., Akinyemiju, T., Ojesina, A. I., Buckhaults, P., Liu, N., Xu, B. & Yi, N. (2017).

Genetics 205, 89-100.

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2016 Publications

The dopamine D3 receptor anatagonist, SR 1502, facilitates extinction of cocaine conditioned place preference.

Galaj, E.; Haynes, J.; Nisanov, R.; Ananthan, S.; Ranaldi, R.

Drug Alcohol Depend. 2016, 159, 263-266

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Alpha-Ketobenzothiazole serine protease inhibitors of aberrant HGF/c-MET and MSP/RON kinase pathway signaling in cancer.

Han, Z.; Harris, P. K.; Karmakar, P.; Kim, T.; Owusu, B. Y.; Wildman, S. A.; Klampfer, L.; Janetka, J. W.

ChemMedChem 2016, 11, 585-599.

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A novel oxazole bearing analogue of combretastatin A-4, disrupts the tumor vasculatures and inhibits the tumor growth via inhibiting tubulin polymerization.

Han, F.; Wang, P.; Zhang, W.; Li, J.; Zhang, Q.; Qi, X.; Liu, M. CA-1H

Biomedicine & Pharmacotherapy, 2016, 80:151-161.

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Pramipexole at a low dose induced beneficial effect in the Harmaline-induced model of essential tremor in rats.

Kosmowska, B.; Wardas, J.; Glowacka, U.; Ananthan, S.; Ossowska, K.

CNS Neurosci. Ther. 2016, 22, 53-62.

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Identification of quinazoline compounds as novel potent inhibitors of Wnt/beta-catenin signaling in colorectal cancer cells.

Li, Y.; Lu, W.; Saini, S.K.; Moukha-Chafiq, O.; Pathak, V.; Ananthan, S.

Oncotarget. 2016, 7, 11263-11270.

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Inhibition of Transforming growth factor-beta activation diminishes tumor progression and osteolytic bone disease in mouse models of multiple myeloma.

Lu, A.; Pallero, M.A.; Lei, W.; Hong, H.; Yang, Y.; Suto, M.J.; Murphy-Ullrich, J.E.

Am. J. Pathol 2016, 186, 678-690.

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Part 1: Notch-sparing gamma-secretase inhibitors: The identification of novel naphthyl and benzofuranyl amide analogs.

Lu, D.; Wei, H. X.; Zhang, J.; Gu, Y.; Osenkowski, P.; Ye, W.; Selkoe, D. J.; Wolfe, M.S.; Augelli-Szafran, C.E.

Bioorgan. Med. Chem. Lett 2016, 26, 2129-2132.

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Acoustic Droplet Ejection Technology and Its Application in High-Throughput RNA Interference Screening.

Nebane, N. M.; Coric, T.; McKellip, S.; Woods, L.; Sosa, M.; Rasmussen, L.; Bjornsti, M. A.; White, E. L.

J Lab Autom. 2016, 21, 198-203.

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An immature myeloid-myeloid-suppressor cell response associated with necrotizing inflammation mediates lethal pulmonary tularemia.

Periasamy, S.; Avram, D.; McCabe, A.; MacNamara, K.C.; Sellati, T.J.; Harton, J.A.

PloS Pathog. 2016 Mar 25, 12(3).

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Acoustic droplet ejection applications for high-throughput screening of infectious agents.

Rasmussen, L.; White, E.L.; Bostwick, J.R.

J Lab Autom. 2016, 21, 188-197.

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Identification of initial leads directed at the calmodulin-binding region on the SRC-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer.

Tzou, Y.M.; Bailey, S.K.; Yuan, K.; Shin, R.; Zhang, W.; Chen, Y.; Singh, R.K.; Shevde, L.A.; Rama, K.N.

Bioorgan. Med. Chem. Lett. 2016, 26, 1237-1244.

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Design and Synthesis of nonpeptide inhibitors of hepatocyte growth factor activation.

Venukadasula, P.K.; Owusu, B.Y.; Bansal, N.; Ross, L.J.; Hobrath, J.V.; Bao, D.; Truss, J. W.; Stackhouse, M.; Messick, T.E.; Klampfer, L.; Galemmo, R.A., Jr.

ACS Med. Chem. Lett 2016, 7, 177-181.

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Part 2. Notch-sparing gamma-secretase inhibitors: The study of novel gamma-amino naphthol alcohols.

Wei, H.X.; Lu, D.; Sun, V.; Zhang, J.; Gu, Y.; Osenkowski, P.; Ye, W.; Selkoe, D.J.; Wolfe, M.S.; Augelli-Szafran, C.E.

Bioorgan. Med. Chem. Lett 2016, 26, 2133-2137.

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Part 3: Notch-sparing gamma-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones.

Zhang, J.; Lu, D.; Wei, H.X.; Gu, Y.; Selkoe, D.J.; Wolfe, M.S.; Augelli-Szafran, C.E.

Chem. Lett 2016, 26, 2138-2141.

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Discovery of novel allosteric Eg5 inhibitors through structure-based virtual screening.

Zhang, W.; Zhai, L.; Lu, W.; Boohaker, R.J.; Padmalayam, I.; Li, Y.

Chem. Biol. Drug Des 2016. doi: 10.1111/cbdd.12744.

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Discovery of a novel inhibitor of kinesin like protein KIFC1.

Zhang, W.; Zhai, L.; Wang, Y.; Boohaker, R.J.; Lu, W.; Gupta, V.V.; Padmalayam, I.; Bostwick, R.J.; White, E.L.; Ross, L.J.; Maddry, J.; Ananthan, S.; Augelli-Szafran, C. E.; Suto, M. J.; Xu, B.; Li, R.; Li, Y.

Biochem. J 2016, 473, 1027-1035.

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A novel cell-based assay to measure activity of Venezuelan equine encephalitis virus nsP2 protease.

Campos-Gomez, J.; Ahmad, F.; Rodriguez, E.; Saeed, M. F.

Virology 2016, 496, 77-89.

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Consortia’s critical role in developing medical countermeasures for re-emerging viral infections: a USA perspective.

Everts, M.; Suto, M. J.; Painter, G. R.; Whitley, R. J.

Future. Virol. 2016, 11, 187-195.

 


 

 Tanzawaic Acids, a Chemically Novel Set of Bacterial Conjugation Inhibitors.

Getino, M.; Fernandez-Lopez, R.; Palencia-Gandara, C.; Campos-Gomez, J.; Sanchez-Lopez, J. M.; Martinez, M.; Fernandez, A.; de la Cruz, C. F.

ONE. 2016, 11, e0148098.

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Pf Filamentous Phage Requires UvrD for Replication in Pseudomonas aeruginosa.

Martinez, E.; Campos-Gomez, J.

mSphere. 2016, 1(1) pii: e00104-15.

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Discovery of Clinically Approved Agents That Promote Suppression of CFTR Nonsense Mutations.

Mutyam, V.; Du, M.; Xue, X.; Keeling, K. M.; White, E. L.; Bostwick, J. R.; Rasmussen, L.; Liu, B.; Mazur, M.; Hong, J. S.; Falk, L. E.; Liang, F.; Shang, H.; Mense, M.; Suto, M. J.; Bedwell, D. M.; Rowe, S. M.

Am. J. Respir. Crit. Care Med. 2016, 194: 1092-1103

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Mycobacterium tuberculosis High-Throughput Screening.

White, E. L.; Tower, N. A.; Rasmussen, L.

Methods Mol. Biol. 2016, 1439, 181-195.

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Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling. 

Owusu, B.Y.; Bansal, N.; Venukadasula, P.K.; Ross, L.J.; Messick, T.E.; Goel, S.; Galemmo, R.A.; Klampfer, L.

Oncotarget. 2016, 7(20):29492-506.

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A sensitive virus yield assay for evaluation of Antivirals against Zika Virus.

Goebel, S.; Snyder, B.; Sellati, S.; Saeed, M.; Ptak, R.; Murray, M.; Bostwick, R.; Rayner, J.; Koide, F.; Kalkeri, R.

J. Virological Methods 2016, 238:13–20.

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Homology modeling of Homo sapiens Lipoic acid Synthase: substrate docking and insights on its binding mode

Krishnamoorthy, E.; Hassan,S.; Hanna, L.E.; Padmalayam, I.; Rajaram, R.; Viswanathan, V.

J. Theoretical Biol. 2016, doi: 10.1016/j.jtbi.2016.09.005.

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Niclosamide and its analogs are potent inhibitors of Wnt/beta-catenin, mTOR and STAT3 signaling in ovarian cancer.

Arend, R. C., Londono-Joshi, A. I., Gangrade, A., Katre, A. A., Kurpad, C., Li, Y., Samant, R. S., Li, P. K., Landen, C. N., Yang, E. S., Hidalgo, B., Alvarez, R. D., Straughn, J. M., Forero, A., and Buchsbaum, D. J. (2016)

Oncotarget 2016, 7:86803-86815

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Recent progress in the combination treatment of radiotherapy and PD-1/PD-L1 signaling blockade immunotherapy

Shang Cai, S., Tian, Y., Xu, B.

Chinese Journal of Radiological Medicine and Protection, 2016, 3:235-240

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Novel Organophosphate Ligand O-(2-Fluoroethyl)-O- (p-Nitrophenyl)Methyl- phosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases.

Chao, C. K., Ahmed, S. K., Gerdes, J. M., and Thompson, C. M.

Chemical research in toxicology 29, 1810-1817

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Diverse arrestin-recruiting and endocytic profiles of tricyclic antipsychotics acting as direct alpha2A adrenergic receptor ligands.

Cottingham, C., Che, P., Zhang, W., Wang, H., Wang, R. X., Percival, S., Birky, T., Zhou, L., Jiao, K., and Wang, Q. (2016)

Neuropharmacology 116, 38-49

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SRI36160 is a specific inhibitor of Wnt/beta-catenin signaling in human pancreatic and colorectal cancer cells.

Li, Y., Oliver, P. G., Lu, W., Pathak, V., Sridharan, S., Augelli-Szafran, C. E., Buchsbaum, D. J., and Suto, M. J. (2016)

Cancer Letters 389, 41-48

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Oxylipins produced by Pseudomonas aeruginosa promote biofilm formation and virulence.

Martinez, E., and Campos-Gomez, J. (2016)

Nature Communications 7, 13823

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CTXɸ: Exploring new alternatives in host factor-mediated filamentous phage replications.

Martinez, E., Campos-Gomez, J., and Barre, F. X. (2016)

Bacteriophage 6, e1128512

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Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

Oliva, C. R., Markert, T., Ross, L. J., White, E. L., Rasmussen, L., Zhang, W., Everts, M., Moellering, D. R., Bailey, S. M., Suto, M. J., and Griguer, C. E. (2016)

The Journal of biological chemistry 291, 24188-24199

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Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia.

Singh, A., Rahman, T., Bartiss, R., Arabshahi, A., Prasain, J., Barnes, S., Musteata, F. M., and Sellati, T. J. (2016)

J. Theoretical Biol. 2016, doi: 10.1016/j.jtbi.2016.09.005.

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Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing.

Zhang, R., Wu, J., Ferrandon, S., Glowacki, K. J., and Houghton, J. A. (2016)

Oncotarget 7: 80190-80207

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2015 Publications

5HT1a receptor binding affinities of a series of serotonin transporter (SERT) inhibitors and related thermodynamic insights.

Alfonsino GE; Santagati A; Baile L; Novellino E; Gaul C; Squires C; Braden M; Gerdes JM; Silanes SP; Guccione S; Parker KK.

Journal of Advances in Medical and Pharmaceutical Sciences 2015, 4:1-12.

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Benzimidazole analogs inhibit respiratory syncytial virus G protein function.

Evans, C. W.; Atkins, C.; Pathak, A.; Gilbert, B. E.; Noah, J. W.

Antiviral Res. 2015, 121, 31-38.

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Radiosynthesis, Rodent and Non-human Primate Studies of a Novel PET Tracer for the Excitatory Amino Acid Transporter 2 (EAAT2) in the CNS.

Gerdes J; Ahmed S; Braden M; Blecha J; VanBrocklin H.

Journal of Nuclear Medicine 2015, 56 (S3):1100.

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Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells.

Khattar, V.; Fried, J.; Xu, B.; Thottassery, J. V.

Cancer Chemother. Pharmacol. 2015, 75, 411-420.

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Phosphodiesterase 10A: A Novel Target for Selective Inhibition of Colon Tumor Cell Growth and ß-catenin-dependent TCF transcriptional activity.

Li, N.; Lee, K.; Xi, Y.; Zhu, B.; Gary, B. D.; Ramirez-Alcantara, V.; Gurpinar, E.; Canzoneri, J. C.; Fajardo, A.; Sigler, S.; Piazza, J. T.; Chen, X.; Andrews, J.; Thomas, M.; Lu, W.; Li, Y.; Laan, D. J.; Moyer, M. P.; Russo, S.; Eberhardt, B. T.; Yet, L.; Keeton, A. B.; Grizzle, W. E.; Piazza, G. A.

Oncogene 2015, 34, 1499-1509.

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Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G.

Pery, E.; Sheehy, A.; Nebane, N. M.; Brazier, A. J.; Misra, V.; Rajendran, K. S.; Buhrlage, S. J.; Mankowski, M. K.; Rasmussen, L.; White, E. L.; Ptak, R. G.; Gabuzda, D.

J. Biol. Chem. 2015, 290, 10504-10517

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Adapting high-throughput screening methods and assays for biocontainment laboratories.

Rasmussen, L.; Tigabu, B.; White, E. L.; Bostwick, R.; Tower, N.; Bukreyev, A.; Rockx, B.; LeDuc, J. W.; Noah, J. W.

Assay. Drug Dev. Technol. 2015, 13, 44-54.

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Effective qPCR Methodology to Quantify the Expression of Virulence Genes in Aeromnonas salmonicida subsp. salmonicida.

Rivera, L.; López-Patiño, M. A.; Milton, D. L.; Nieto, T. P.; Farto, R.

Appl.Microbiol. 2015, 118, 792-802.

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Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency.

Rothman, R. B.; Ananthan, S.; Partilla, J. S.; Saini, S. K.; Moukha-Chafiq, O.; Pathak, V.; Baumann, M. H.

Pharmacol. Exp. Ther. 2015, 353, 529-538.

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Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Schreiber, S. L.; Kotz, J. D.; Li, M.; Aube, J.; Austin, C. P.; Reed, J. C.; Rosen, H.; White, E. L.; Sklar, L. A.; Lindsley, C. W.; Alexander, B. R.; Bittker, J. A.; Clemons, P. A.; de, S. A.; Foley, M. A.; Palmer, M.; Shamji, A. F.; Wawer, M. J.; McManus, O.; Wu, M.; Zou, B.; Yu, H.; Golden, J. E.; Schoenen, F. J.; Simeonov, A.; Jadhav, A.; Jackson, M. R.; Pinkerton, A. B.; Chung, T. D.; Griffin, P. R.; Cravatt, B. F.; Hodder, P. S.; Roush, W. R.; Roberts, E.; Chung, D. H.; Jonsson, C. B.; Noah, J. W.; Severson, W. E.; Ananthan, S.; Edwards, B.; Oprea, T. I.; Conn, P. J.; Hopkins, C. R.; Wood, M. R.; Stauffer, S. R.; Emmitte, K. A.

Cell 2015, 161, 1252-1265.

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Development of a human live attenuated West Nile infectious DNA vaccine: Conceptual design of the vaccine candidate.

Yamshchikov, V.

Virology 2015, 484, 59-68.

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High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.

Yang, B.; Ming, X.; Cao, C.; Laing, B.; Yuan, A.; Porter, M. A.; Hull-Ryde, E. A.; Maddry, J.; Suto, M.; Janzen, W. P.; Juliano, R. L.

Nucleic Acids Res. 2015, 43, 1987-1996.

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Elevated Aurora B expression contributes to chemoresistance and poor prognosis in breast cancer.

Zhang, Y.; Jiang, C.; Li, H.; Lu, F.; Li, X.; Qian, X.; Fu, L.; Xu, B.; Guo, X. Int.

J. Clin. Exp. Pathol. 2015, 8, 751-757.

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Mutation of the BRCA1 SQ-cluster results in aberrant mitosis, reduced homologous recombination, and a compensatory increase in non-homologous end joining.

Beckta, J. M.; Dever, S. M.; Gnawali, N.; Khalil, A.; Sule, A.; Golding, S. E.; Rosenberg, E.; Narayanan, A.; Kehn-Hall, K.; Xu, B.; Povirk, L. F.; Valerie, K.

Oncotarget 2015, 6:27674-27687.

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The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats.

Galaj, E.; Manuszak, M.; Babic, S.; Ananthan, S.; Ranaldi, R.

Drug Alcohol Depend. 2015, 156:228-233

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K-Ras, intestinal homeostasis and colon cancer.

Goel, S.; Huang, J.; Klampfer, L.

Curr. Clin Pharmacol. 2015, 10:73-81.

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Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer.

Owusu, B. Y.; Vaid, M.; Kaler, P.; Klampfer, L.

Biomark. Cancer 2015, 7:29-37.

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Acoustic Droplet Ejection Applications for High-Throughput Screening of Infectious Agents.

Rasmussen, L.; White, E. L.; Bostwick, J. R.

J Lab Autom. 2016, 21:188-197.

Click here to download pdf.


 

Challenges and Opportunities for Molecular Radiation Biology in the Era of Precision in Medicine.

Shang, C.; Ye, T.; Xu, B.

Chinese J of Radiation Oncology, 2015, 24:729-731.

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Suppression of beta-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.

Li, N.; Chen, X.; Zhu, B.; Ramirez-Alcantara, V.; Canzoneri, J. C.; Lee, K.; Sigler, S.; Gary, B.; Li, Y.; Zhang, W.; Moyer, M. P.; Salter, E. A.; Wierzbicki, A.; Keeton, A. B.; Piazza, G. A.

Oncotarget 2015, 6:27403-27415.

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KIFC1 is a novel potential therapeutic target for breast cancer.

Li, Y.; Lu, W.; Chen, D.; Boohaker, R. J.; Zhai, L.; Padmalayam, I.; Wennerberg, K.; Xu, B.; Zhang, W.

Cancer Biol. Ther. 2015, 16:1316-1322

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Temperature-sensitive Polymersomes for Controlled Delivery of Anticancer Drugs.

Liu, F.; Kozlovskaya, V.; Medipelli, S.; Xue, B.; Ahmad, F.; Saeed, M.; Cropek, R.; Kharlampieva, E.

Chem. Mater. 2015, 27:7945-7956

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A radiosensitivity MiRNA signature validated by the TCGA database for head and neck squamous cell carcinomas.

Liu, N.; Boohaker, R. J.; Jiang, C.; Boohaker, J. R.; Xu, B.

Oncotarget. 2015, 6:34649-34657.

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Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation.

Venukadasula, P.; Owusu, B. Y.; Bansal, N.; Ross, L. J.; Hobrath, J. V.; Bao, D.; Truss, J. W.; Stackhouse, M.; Messick, T.; Klampfer, L.; Galemmo, R. A., Jr.

ACS Med.Chem.Lett. Publication Date (Web) December 22, 2015

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Intracellular Degradable Hydrogel Cubes and Spheres for Anti-cancer Drug Delivery.

Xue, B.; Kozlovskaya, V.; Liu, F.; Chen, J.; Williams, J.; Campos-Gomez, J.; Saeed, M.; Kharlampieva, E.

ACS Appl Mater Interfaces, 2015, 7:13633-16344.

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A MicroRNA Expression Signature In Taxane-anthracycline-Based Neoadjuvant Chemotherapy Response.

Zheng, Y.; Li, S.; Boohaker, R. J.; Liu, X.; Zhu, Y.; Zhai, L.; Li, H.; Gu, F.; Fan, Y.; Lang, R.; Liu, F.; Qian, X.; Xu, B.; Fu, L.

J Cancer, 2015, 6:671-677.

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Research Partnerships & Collaborations

The Alabama Drug Discovery Alliance (ADDA), which began in 2009, is a coordinated drug discovery and development program that unites the talents and resources of Southern Research and the University of Alabama at Birmingham (UAB)’s School of Medicine, Center for Clinical and Translational Sciences, and the Comprehensive Cancer Center. The ADDA is a strategic institutional collaboration which aims to support the discovery and development of therapeutic molecules that address unmet medical needs, developing promising new therapies for debilitating diseases. Its discovery pipeline includes potential therapies for Parkinson’s disease, diabetes, kidney disease, Alzheimer’s, and many types of cancers. The ADDA is seen as filling a critical gap in the drug discovery process given that pharmaceutical companies are increasingly reluctant to invest in the necessary — but risky — basic research that leads to an approved treatment.

 

Researchers from either Southern Research or UAB can apply for ADDA support; the programs are vetted and accepted based upon stringent criteria such as novelty, rationale, medical need and translational potential. After acceptance, projects are milestone-driven and managed by a project team consisting of scientists from both institutions. The focus of the ADDA is pre-clinical development, with programs advancing from target validation through IND-enabling studies. Successful compounds with proof-of-principle data may be advanced into Phase I clinical trials. The alliance has the commitment of both institutions’ respective technology transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts. The alliance has received substantial local and international support (i.e., Birmingham-based Protective Life, Dai-ichi Life Insurance Co. of Japan).

 

To be updated about ADDA activities and funding opportunities, you can request to be added to ADDA’s email distribution list. For any questions, please contact:

Mark Ravera, P: 609-226-0369

The mission of the Center for Clinical and Translational Science (CCTS) is to address disparities and diseases disproportionately represented within the Deep South. The CCTS is the Clinical and Translational Science Awards (CTSA) Hub based at the University of Alabama at Birmingham (UAB), which serves a region and a population heavily burdened with obesity, diabetes, cancer, cardiovascular disease and stroke. The vision of the CCTS is to ameliorate disparities in these and other conditions that disproportionately affect minority and special populations represented within our region and across the nation. To achieve these goals, the CCTS Hub has developed a Partner Network of academic centers and research institutes, including Southern Research, in the Deep South to better serve special populations while maximizing collaborative synergies in translational research.

The cornerstone of the CCTS Partner Network drug discovery program is collaboration with Southern Research, through which investigators can access unique capabilities and expertise in high throughput screening and medicinal chemistry. Among those available through Southern Research (i.e., high throughput robotics, compound libraries and medicinal chemistry), over one million small molecules for screening, together with a library of 2500 FDA approved drugs and 460 compounds that have been advanced previously to clinical testing in other contexts (but failed in a specific disease indication for mechanistic reasons) are available. Identified “hits” from the clinical compound libraries are of high value since they have already been tested in human subjects for another indication and de-risked in support of drug repurposing efforts.

For additional information see:

http://www.uab.edu/ccts/

 

The Antiviral Drug Discovery and Development Center (AD3C), coordinated out of the University of Alabama at Birmingham (UAB), is one of 14 Centers of Excellence for Translational Research (CETR) designated by the National Institute of Allergy and Infectious Diseases (NIAID). The goal of AD3C is to advance the discovery, preclinical development, production, licensure and/or use of new or improved medical countermeasures (therapeutics, immunotherapeutics, vaccines, vaccine technologies, and medical diagnostics) or related technologies for emerging and re-emerging infectious diseases. Each multi-project Center is organized around a specific theme that addresses development of a targeted medical countermeasure or technology, and related regulatory barriers. Supported translational activities range from very early discovery-based efforts to late-stage preclinical development.

Southern Research is among the various institutions working with UAB to perform this important research. The families of viruses targeted within the AD3C are of the highest priority for the U.S. government, both as biologic threats and unmet medical needs. The AD3C focuses on developing drugs for four virus families: influenza, flaviruses, coronaviruses and alphaviruses—viruses causing diseases including West Nile, SARS, chikungunya and dengue. The goal is to identify compounds working through mechanisms that affect viral replication and develop these leads in a translational manner to new human therapeutics. Researchers work to target and inhibit enzymes essential for viral replication, with AD3C providing an infrastructure to accelerate the development of new potential drugs from the lab towards the clinic.

For grant support and additional information see:

1U19AI109680            Project #: 14246             PI: Richard Whitley     https://projectreporter.nih.gov/project_info_description.cfm?aid=8641766&icde=32409602

 

The Cystic Fibrosis (CF) Foundation, a donor-funded, 501(c)(3) non-profit, is the world’s leader in the search for a cure for CF, and nearly every CF-specific drug available today was made possible with financial support provided by the CF Foundation. CF is a life-threatening, genetic disease that affects approximately 30,000 people in the U.S., with almost 1,000 new cases each year, and nearly 70,000 people worldwide. Through the CF Foundation’s efforts, the life expectancy of people with CF has doubled in the past 30 years and research to find a cure is more promising than ever. Southern Research works to meet the mission of the CF Foundation, which is to find a cure and to provide all people with the disease the opportunity to lead full, productive lives.

Southern Research’s High Throughput Screening Center, University of Alabama at Birmingham (UAB), and CF Foundation Therapeutics, Inc. (CFFT), have been working together for several years investigating the repurposing of known drugs for the treatment of CF. CFFT, a non-profit drug discovery and development affiliate of the CF Foundation, supports and governs activities related to CF drug discovery through the many stages of drug development and clinical evaluation. CFFT has ramped up its efforts to pursue cutting-edge strategies that target nonsense and other mutations by addressing earlier cellular processes that generate the malfunctioning cystic fibrosis transmembrane conductance regulator (CFTR) protein. Research has shown that nonsense mutations in the cftr gene, which occurs in about ten percent of individuals with CF, cause messenger RNA molecules to transmit a signal to stop production of the CFTR protein too early. This premature stop signal results in a shortened, and often non-functional, CFTR protein. In individuals with CF, a defective CFTR protein leads to the build-up of thick mucus, which in turn leads to persistent lung infections and complications in other parts of the body. Identification of Therapeutics for CF (PI: Steven Rowe) is a milestone driven, comprehensive five-year drug discovery collaborative effort between Southern Research and UAB, supported by CFFT, to find new therapies for CF patients with a nonsense mutation. Southern Research has incorporated a sophisticated screening process to identify compounds in our chemical library that could promote the production of functional CFTR protein. Using special tests developed by UAB, we are seeking compounds that would override that premature stop signal, allowing fully functional protein to be made. We are also looking for compounds that would address other problematic cellular processes.

 

For grant support and additional information see:

Cystic Fibrosis Foundation: https://www.cff.org/

https://www.cff.org/News/News-Archive/2015/CFFT-Announces-Award-to-Discover-New-Nonsense-Mutation-Therapies/

http://www.prnewswire.com/news-releases/southern-research-receives-75-million-award-to-discover-new-therapies-for-cystic-fibrosis-patients-with-rare-mutations-300163427.html?tc=eml_cleartime

 

The Muscular Dystrophy Association (MDA) is leading the fight to free individuals from the harm of muscular dystrophy, amyotrophic lateral sclerosis (ALS) and related muscle-debilitating diseases that take away physical strength, independence and life. ALS is a neuromuscular disease which affects 1-2 people in every 100,000. The disease causes degeneration of motor neurons, paralysis and death. The disease is characterized by superoxide dismutase 1 (SOD1) abnormalities that results in an excess of reactive oxygen species (ROS) and mitochondrial damage. Southern Research has worked with the MDA to identify small molecules that could be further developed for use in the treatment of ALS. Our drug discovery work, involving a high throughput screening campaign, has led to novel molecules which can alter SOD1 activity through its effects in brain cells, and therefore ameliorate the disease outcome. These molecules have shown significant prolongation of life expectancy, decreased weight loss and improved neurologic symptoms. Current efforts have identified novel orally bioavailable compounds working through the same mechanism. This work was published in the Journal of Neuroscience Research. Our efforts to develop novel molecules based on these compounds are on-going.

 

For grant support and additional information see:

https://www.mda.org/

https://www.mda.org/sites/all/themes/mda_bootstrap_subtheme/pdf/ActiveGrantsAugust2016.pdf

 

The BrightFocus Foundation is a non-profit organization that works to save mind and sight through their mission to drive innovative research and to promote awareness to end Alzheimer’s disease (AD), macular degeneration, and glaucoma, and to encourage the public to take action to better manage their health. “Development of Inhibitors of the Tau-Fyn Interaction for the Treatment of Alzheimer’s disease” is a collaborative project between the University of Alabama (UAB; PI: Erik Roberson) and Southern Research to identify a novel therapy for treating AD. Taking an approach that represents a new therapeutic strategy for treatment of AD, compounds are being investigated that would stop the interaction between two proteins, Tau and Fyn. Tau is widely considered an excellent target for AD, but it is unclear how to target it. Normally Tau serves a physiologic role in humans, including stabilizing microtubule structures that are important for transporting molecules throughout the neuron. However, while we know that Tau is involved in AD, we don’t yet know exactly how Tau contributes to the disease. A variety of data indicate that Tau’s interaction with another protein known as Fyn tyrosine kinase may be critical. Tau and Fyn bind with each other, and a variety of data indicate that Fyn is directly involved in AD as well. We are investigating compounds that would stop the interaction between Tau and Fyn. We have screened approximately 100,000 compounds and identified several initial hits that specifically block the interaction. The next phase of the project is to further evaluate and refine these hits to develop lead compounds for evaluation in animal models. If successful, this work could help identify a new therapeutic approach to AD.

 

For grant support and additional information see:

http://www.brightfocus.org/alzheimers/grant/development-inhibitors-tau-fyn-interaction-treatment-alzheimers-disease

 

The Steven & Alexandra Cohen Foundation, established in 2001 in Connecticut by Steven A. Cohen and his wife, Alexandra, is committed to inspiring philanthropy and community service by creating awareness, offering guidance, and leading by example to show the world what giving can do. Focus areas include children’s health; educational reform; support of military veterans and their families; art education programs; services for families in need, first responders, and other public service organizations in the local community; and the combat of Lyme disease. The Foundation’s commitment to Lyme disease, which includes donations of over $40 million for more than 20 Lyme disease projects, has led to the selective investment of funds to support Southern Research’s endeavors to combat this complex illness.

As many as 15% of patients diagnosed with Lyme disease, caused by the tick-borne bacterial spirochete Borrelia burgdorferi, develop neurological complications referred to as neuroborreliosis. Peripheral symptoms manifest as radiculopathy, while central nervous system (CNS) involvement typically engenders meningitis and cognitive deficits of varying severity. Whether the severity of brain tissue injury and disease progression reflects the proximity of spirochetes is currently unknown. This knowledge gap is due, in part, to a lack of fine-scale analysis of the brain lesions of neuroborreliosis patients.

With the Foundation’s support, we will conduct a retrospective analysis of formalin-fixed brain sections for specific immune cells, markers of inflammation, and bacteria to compare and contrast neuropathy in patients diagnosed with Lyme disease versus non-infectious neurological etiologies. Execution of the proposed study will advance our understanding of the role of inflammatory mediators in the pathogenesis of neuroborreliosis by possibly linking its production to the presence of B. burgdorferi in neurological lesions. Such knowledge will facilitate the development of novel treatment strategies to alleviate the ongoing neuropsychiatric symptoms suffered by some Lyme disease patients.

For grant support and additional information see:

http://www.steveandalex.org/

Education and Training Programs

Southern Research has been actively participating in training the next generation of scientists since its founding in 1941. The research laboratories in the Drug Discovery Division accept trainees including graduate students, postdoctoral fellows as well visiting scholars.

UAB Graduate Biomedical Sciences Program

Southern Research provides interdisciplinary training experiences for the University of Alabama at Birmingham (UAB) Graduate Biomedical Sciences (GBS) Program, which encompasses approximately 440 graduate students and 350 faculty. Southern Research is a part of a broad network of multiple interdisciplinary thematic programs which integrates more than 25 departments and 20 research centers at UAB, as well within the biotechnology institute, HudsonAlpha. Southern Research offers the students of the GBS Program a broad spectrum of research opportunities related to drug discovery.

This partnership to-date has allowed for numerous graduate students to complete their doctoral thesis research in Southern Research labs. Various faculty members in Southern Research’s drug discovery division hold academic appointments in departments at the UAB School of Medicine as well as serve as training members of the UAB Graduate School. Collectively, the synergy generated through this partnership has the capacity to nurture the next generation of scientific leaders.

 

Postdoctoral Training

Postdoctoral training is a major training mission in the Drug Discovery Division. For individual’s with a doctoral degree (PhD, MD, DDS, or the equivalent), Southern Research offers a number of postdoctoral training opportunities in the areas of Oncology, Infectious Diseases, and Medicinal Chemistry. These opportunities allow the trainee to be engaged in mentored research and/or scholarly training for the purpose of acquiring the professional skills needed to pursue a career path of his or her choosing. As such, this position allows the research trainee to enhance and develop research competencies through participation in planning, designing and conducting highly technical and complex research projects under the supervision of a Principal Investigator in the Drug Discovery Division. The trainee also participates in all aspects of data collection, analysis and interpretation, often resulting in peer-reviewed publications.  Postdoctoral experiences offered by Southern Research equips the trainees to lead scientific discovery as the next generation of scientific leaders. Many Southern Research postdoctoral trainees have advanced their scientific careers to become independent researchers in both academia and industry.

 

International J1 Training Program

In October 2013, in collaboration with the American Immigration Council, we initiated a J-1 Visa training program for international trainees. The program allows international scholars to learn in Southern Research Drug Discovery laboratories for up to 18 months of training on biomedical research. As such, Southern Research’s mission of education fosters international collaborations for future research in precision medicine.

 

Research Internship

Southern Research offers a Research Internship program to college students from across the U.S., which provides firsthand experience with the innovative work conducted across the Drug Discovery Division. Interns from Princeton University, Emory University, the University of Virginia, Birmingham-Southern College, the University of Alabama, and the University of Alabama at Birmingham (UAB) are among those who have participated and gained experience similar to that found in potential future careers.

Throughout the term, the students work with a mentor and do a presentation or write a research report at the end of the term. For the interns, the experience offered real-world work experience in a lab setting. The internship program also helps Southern Research attract more talented people to join the nonprofit. In general, most students do research for course credits. Southern Research also has paid interns during the Summer months which allows the students to gain additional experience outside of the classroom.

The internship program within each department at Southern Research offers a variety of opportunities. Upon completion of the internship, the trainees learn how to design, execute, and analyze hypothesis-driven experiments in the field of drug discovery.


Science, Technology, Engineering and Math (STEM) Education

In line with the priority set at the national level to increase the number of students and teachers who are proficient in the vital fields of science, technology, engineering, and math, subjects collectively known as STEM, Southern Research hosts STEM Day event. Through this experience, future scientists, selected based on their interest and achievements in the fields of science, technology, engineering and mathematics, receive exposure and hands-on participation to learn about careers in science. Students from across the Birmingham metro area learn about the types of careers they can pursue with an interest in science, focusing on Drug Discovery, Drug Development, Energy & Environment and Engineering. They are broken into groups and are led by Southern Research Staff in various experiments and operations tours where they are given a behind-the-scenes look at the innovative work being done by the Birmingham-based nonprofit’s scientists and engineers.

Students walk through the steps involved in anti-cancer drug discovery and testing, specifically synthesizing and evaluating aspirin as a treatment and determining the viability of cancer cells. They also learn how to grow and study bacteria in the lab. In addition, they perform destructive and non-destructive tests on metal materials and observed demonstrations of power plant operations, control loop integration and flue gas treatment.

The purpose of Southern Research’s participation in the STEM Day event is multi-fold. The program helps Southern Research in its philanthropic mission while simultaneously engaging the community and young, budding scientists and engineers, which ultimately helps establish a pipeline of future job candidates.

Drug Discovery News