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ADDA DISCOVERY PIPELINE

Click on each program for details.

 
  • HTS
  • HIT VALIDATION
  • LEAD IDENTIFICATION
  • LEAD DEVELOPMENT
  • PRECLINICAL
  • PHASE 1
CNS
Alzheimer’s Disease
Parkinson’s Disease
Parkinson’s Disease
ONCOLOGY
Various Cancers
Glioblastoma
Multiple Myeloma & CLL
Multiple Myeloma & Fibrosis
Myelodysplastic Syndrome
Leukemias
Radiation Sensitizer
RESP
Tuberculosis
OTHER
Kidney Disease
Diabetes
Hurler Syndrome
14-3-3 is a family of chaperone proteins that have been implicated in some neurodegenerative disorders including Parkinson's Disease (PD). 14-3-3 proteins interact with α-synuclein and may be a bridge between that protein and PD. Several isoforms of 14-3-3 are down-regulated in a transgenic mouse model of PD; up-regulation in these models is neuroprotective. We are currently evaluating testing a set of first-in-class molecules identified through our HTS efforts to identify the most potent and selective for transcription activation of 14-3-3.
The interaction between Tau and Fyn has been shown to have a pathogenic role in Alzheimer’s Disease. We have identified several potential lead compounds with high selectivity and excellent drug-like properties. Secondary assays have confirmed that these first-in-class compounds protect neurons from Aβ-related toxicity.
Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene can cause late-onset Parkinson’s Disease (PD). The LRRK2 gene encodes a protein with kinase activity, and the mutations that cause PD increase this kinase activity, linking elevated kinase activity to PD susceptibility. Therefore selective inhibition of elevated kinase activity may be beneficial in halting disease progression. We have identified a highly selective brain penetrating compound with excellent drug-like properties that inhibits LRRK2 kinase both in vitro and in vivo. Further medicinal chemistry efforts are now underway.
RNA Polymerase I (Pol I) is responsible for transcription of ribosomal RNA (rRNA) which forms the bulk of a ribosome. Ribosome synthesis, and therefore Pol I transcription, is proportional to the growth rate of tumor cells. This makes Pol I is an excellent biological target for controlling cell growth and proliferation rates. Drugs that specifically target Pol I could be a major component of future cancer chemotherapeutic approaches.
First-line therapy for glioblastoma is temozolomide (TMZ), but most tumors develop resistance to the drug. Cytochrome C Oxidase (CcO) levels are increased in TMZ-resistant tumors; inhibition of CcO reverses TMZ resistance in vitro. Our HTS efforts have identified two lead compounds that inhibit CcO activity. In vivo, these compounds partition to the CNS and significantly extend the lifespan of animals with TMZ-resistant glioblastoma. Medicinal chemistry is ongoing, as are additional in vivo studies looking at various dosing regimens.
CD38 has an ectoenzyme function that controls NAD/NADH and NADP/NADPH metabolism in B cells. Inhibition of this enzymatic function would make malignant B cells more susceptible to reactive oxygen species generated both metabolically and by chemotherapeutic agents. We have identified three chemical series that are potent and selective inhibitors of the CD38 ectoenzyme and further characterization is underway.
In multiple myeloma, TSP1 activates the latent form of TGF-β, making TSP a key control point for disease progression. We have identified a stabilized tripeptide, SRI-31277, that inhibits TSP1 activation of TGF-β in murine models of human multiple myeloma. In these models, SRI-31277 reduces myeloma tumor burden and TGF-β activity in the bone marrow. It also increases tibial osteoblast numbers in a systemic SCID mouse model, demonstrating efficacy at least equal to that of dexamethasone. Additional studies are underway examining the potential of SRI-31277 in various fibrotic diseases
Inhibition of DNA methylation through depletion of DNA methyltransferase (DNMT1) results in increased expression of tumor suppressor genes. While there are two approved drugs (decitabine and azacytidine) that target DNMT1, these agents have low response rates and are associated with considerable toxicities. We have identified two new molecules that have the potency of decitabine in pre-clinical models but with much lower levels of toxicity. Under an IND filed by the NCI, Phase I studies are nearing completion.
Iron is an essential nutrient for Mycobacterium tuberculosis (M. tb) but is often sequestered by the host. M. tb secretes siderophores, small molecules with extremely high iron binding affinities, to acquire host iron. We have shown that genetically eliminating siderophore secretion reduces M. tb's virulence in vivo by 10,000 fold. HTS has identified a number of small molecules that appear to block siderophore secretion. Confirmatory assays of these first-in-class compounds are now underway.
Heme Oxygenase-1 is an anti-inflammatory, anti-apoptotic, and immune modulatory protein. It has been shown to be a potent cytoprotective enzyme in diverse conditions including renal injury, diabetes, sickle cell disease, organ transplantation, sepsis, and ischemia reperfusion injury. We have identified five chemical series that are both potent and selective activators of this enzyme. Further characterization of these first-in-class compounds is on-going.
Thioredoxin-interacting protein (TXNIP) is increased in pancreatic islets of diabetic mice. Over-expression of TXNIP induces beta cell apoptosis, and plays a critical role in linking glucose toxicity to beta cell death. SRI-33597 is a first-in-class compound that inhibits TXNIP expression resulting in stabilized beta cell function and reduced beta cell apoptosis in diabetic mouse models.
DPY30 is a subunit of the histone H3K4 methyltransferase complex, and inhibitors of DPY30 have potential in treating MYC-dependent hematologic malignancies. We have identified several series of compounds specifically block the interaction of DPY30 with the methyltransferase complex, and shown that these compounds inhibit MYC transcriptional activity and impair leukemia cell growth in vitro. Further characterization of these compounds is now underway.
Ionizing radiation (IR) is a key component of cancer therapy, and making tumor cells more sensitive to IR would improve therapeutic outcomes and long-term survival. One key element in the cellular response to IR is ATM kinase. To fully function in the cellular response to IR, ATM needs to be activated, which requires interaction with the NBS1 protein. Our HTS efforts have identified a number of small molecules that specifically block the NBS1-ATM interaction at sub-micromolar concentrations. Further characterization of these compounds, with parallel efforts in medicinal chemistry, are now underway.
Mucopolysaccharidosis I-Hurler (MPS I-H) is an autosomal recessive lysosomal storage disease that results from an in-frame premature termination codon (PTC), also known as a nonsense mutation. The development of safe, effective read-through (PTC-suppressing) drugs could complement (or ultimately replace) current MPS I-H treatments. Our efforts in MPS I-H are part of a larger multi-therapeutic area HTS effort to identify compounds for PTC-related diseases. From these screening efforts, we expect to identify chemical scaffolds that show efficacy in our MPS I-H model systems.