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 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, making 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 vivo fibrosis studies with SRI-40000 are now underway.
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.
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-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.
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.