Drug DiscoveryContact Us
Southern Research Drug Discovery is an active participant in and worldwide leader of ongoing drug discovery programs targeting various forms of cancer, a wide variety of neurologic and metabolic diseases, and a host of imminent viral and bacterial infections. We are a team of approximately 75 scientists who conduct basic research with a translational component as we identify small molecules that may become novel therapeutics for today’s most significant healthcare challenges. The multidisciplinary nature of drug discovery research is facilitated by Southern Research’s collaborative integration of biology, high throughput screening, and chemistry. In brief, a novel target is identified by our internal biological sciences group or through a collaboration, and a validated assay is established, which can then be used by our High Throughput Screening team on a large scale to identify “hits” for further investigation. Our Chemistry Department develops those hits to be more drug-like molecules through medicinal chemistry efforts, and eventually, synthesizes a potential drug. It can then be taken back to biological sciences for confirmation through mechanism of action studies and secondary assay performance. Eventually, these drug candidates are taken into clinical studies.
Aligned with our vision to lead and empower drug discovery, our internal research efforts are augmented by many collaborative relationships and external partnerships, including those from academic and industrial institutions. Our team-based system can be well-integrated into multi-centered project teams, as exemplified by ongoing projects. For example, a strong relationship exists with University of Alabama at Birmingham, through the Alabama Drug Discovery Alliance, launched in 2008 to facilitate and expedite the discovery and development of new drug therapies. We have formed a similar partnership with the University of Tennessee Health Science Center to advance promising research that could lead to new drugs that address unmet medical needs. Moreover, we are working to develop a new anti-cancer drug with Bionetix, a South Korean biotechnology company, through our newly developed collaborative research program. The division is also funded by multiple centers of the National Institutes of Health and other federal institutions, such as the Department of Defense. In addition, we have secured funding from several foundations such as the Cystic Fibrosis Foundation, Muscular Dystrophy Foundation, BrightFocus Foundation, Amyotrophic Lateral Sclerosis Association, Steven & Alexandra Cohen Foundation, Michael J. Fox Foundation, and Rheumatology Research Foundation.
Drug Discovery Departments
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
PD1 Small Molecule Inhibitors for Oncology
Immuno-Oncology (I/O) is becoming increasing important part of cancer treatment. All of the currently approved I/O drugs are monoclonal antibodies. Small molecule I/O drugs offer several advantages over monoclonal antibodies, including lower cost and the potential for oral and topical uses, extending the range of indications for these inhibitors beyond oncology.
We have identified small molecules that inhibit PD1-PDL1 binding. Cell co-culture assays show that our compounds have activity (T-cell proliferation, cytokine modulation, etc.) similar to that of pembrolizumab. Head-to-head in vivo studies also show activity that parallels the activity of pebrolizumab.
GLI1 Inhibitors for Solid Tumors
GLI1 is a transcription activator that is part of the K-RAS pathway. Certain cancers (including pancreatic and colorectal) can be dependent on GLI1 activity, but GLI1 is not required by normal (non-cancerous) tissue. We have identified small molecule inhibitors of GLI1 that inhibit growth of a chemotherapy-resistant tumor in vivo. Tests with a range of other tumor types are being planned for this first-in-class program.
- “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”
- “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
- “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
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:
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/
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:
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:
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:
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 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.
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.
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Chem. Biol. Drug Des 2016. doi: 10.1111/cbdd.12744.
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Biochem. J 2016, 473, 1027-1035.
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Virology 2016, 496, 77-89.
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ONE. 2016, 11, e0148098.
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Oncotarget 2016, 7:86803-86815
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
Chao, C. K., Ahmed, S. K., Gerdes, J. M., and Thompson, C. M.
Chemical research in toxicology 29, 1810-1817
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Cancer Letters 389, 41-48
Martinez, E., and Campos-Gomez, J. (2016)
Nature Communications 7, 13823
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Bacteriophage 6, e1128512
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The Journal of biological chemistry 291, 24188-24199
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Oncotarget 7: 80190-80207
5HT1a receptor binding affinities of a series of serotonin transporter (SERT) inhibitors and related thermodynamic insights.
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Oncogene 2015, 34, 1499-1509.
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Cell 2015, 161, 1252-1265.
Virology 2015, 484, 59-68.
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.
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Galaj, E.; Manuszak, M.; Babic, S.; Ananthan, S.; Ranaldi, R.
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Oncotarget 2015, 6:27403-27415.
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
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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Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation.
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ACS Appl Mater Interfaces, 2015, 7:13633-16344.
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J Cancer, 2015, 6:671-677.
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