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ADDA DISCOVERY PIPELINE

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  • HTS
  • HIT VALIDATION
  • LEAD IDENTIFICATION
  • LEAD DEVELOPMENT
  • PRECLINICAL
  • PHASE 1
CNS
Alzheimer’s Disease
Parkinson’s Disease
ONCOLOGY
Multiple Myeloma & Fibrosis
Myelodysplastic Syndrome
Leukemias
OTHER
Diabetes
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 the mechanism of action and shown that these first-in-class compounds protect neurons from Aβ-related toxicity.
Over-activity of different forms of the Leucine-Rich Repeat Kinase 2 (LRRK2) gene has been associated both with late-onset Parkinson’s Disease (PD) and with idiopathic PD (the most common form). Therefore selective inhibition of elevated LRRK2 kinase activity may be beneficial in halting disease progression. We have identified a series of very potent, highly selective LRRK2 inhibitors with excellent drug-like properties and good CNS penetration. A US patent has recently been issued on this series, and lead optimization studies are continuing.
In fibrosis and several tumor types, TSP1 activates the latent form of TGF-β in the extracellular matrix thereby adding to the disease cascade; this makes TSP a key control point for disease progression. We have identified both peptides (SRI-32177) and small molecules (SRI-40000) that specifically inhibit TSP1 activation of latent TGF-β. In two murine models of fibrosis (diabetic nephropathy and diabetic cardiomyopathy), SRI-31277 demonstrates significant fibrosis reduction and improvement in organ function. In murine models of multiple myeloma, both SRI-31277 and SRI-40000 significantly reduce tumor burden. In a murine model of idiopathic pulmonary fibrosis, SRI-40000 significantly reduces disease severity.
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.
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-37330 is a first-in-class compound that inhibits TXNIP expression and offers a potentially new treatment modality for diabetes. SRI-37330 improves overt diabetes in both an STZ model and in a db/db model while protecting beta cell mass. In healthy mice, SRI-37330 is well tolerated, with animals maintaining both normal blood glucose and serum insulin levels.
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 kill myc-dependent leukemia cells in vitro while not killing non-myc dependent cells. Further characterization of these compounds is now underway.