Developing Inhibitors of the STARS/SRF Pathway for Treatment of Type 2 Diabetes

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DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has reached epidemic proportions in the United States, affecting an estimated 8.3% of the population. Unfortunately, the majority of individuals with diabetes continue to have suboptimal control of glucose, therefore new and improved approaches to prevention and treatment are sorely needed. Dr. Mary Elizabeth Patti's laboratory at the Joslin Diabetes Center (JDC) has recently identified a novel pattern of gene expression in skeletal muscle from human patients with established T2D. This pattern includes increased expression of genes regulated by serum response factor (SRF) and its upstream regulatory protein STARS (striated muscle activator of Rho-dependent signaling). Importantly, this pattern is also present in those at risk for disease based on family history, potentially linking this to T2D-risk. Genetic and pharmacologic data from the Patti lab (JDC) robustly indicate that modulation of the STARS-SRF pathway can regulate muscle insulin resistance and metabolism, and thus may serve as an important target for novel drug development strategies for diabetes management. Inhibition of STARS-SRF in cultured myotubes by either reduced expression of STARS or use of the small molecule SRF inhibitor CCG-1423 improves oxidative metabolism and increases insulin stimulated glucose transport. Moreover, inhibition of this pathway in mice also improves metabolic outcomes: (1) STARS-null mice are resistant to diet-induced obesity and glucose intolerance, potentially via increased exercise capacity and energy expenditure (and appear healthier) and (2) treatment of mice with the SRF inhibitor CCG-1423 normalizes glucose tolerance in mice with diet-induced obesity. In this Phase I, Jenesis Biosciences (formerly Joslin Ventures, LLC) will further validate and characterize this exciting new target in collaboration with Dr. Patti (JDC) for its therapeutic utiity. We already have two SRF- inhibitors (CCG-1423 and its analog, 203,971) that will be used to a) elucidate the precise molecular target, b) investigate mechanism dependent toxicity in vitro, and c) demonstrate in vivo proof-of-concept in both diet- induced and genetically predisposed mouse models (and evaluate in vivo toxicity). Completion of this Phase I proposal, will enable us to conclusively assess whether this pathway is amenable to medicinal intervention. This will be achieved by studying mechanism-dependent toxicity and understanding the therapeutic window of CCG-compounds. CCG-203,971 appears to have 3x greater potency (d0.15mg/kg/day), improved solubility and does not appear to show adverse effects in a pilot in vivo study at 100mg/kg/day (for a week) indicating an excellent therapeutic window. This information coupled with its target affinity (ITC-derived Kd) will be used to assess its potential as a Lead compound for Medicinal Chemistry optimization in Phase 2, where more potent, drug-like analogs will be generated and evaluated for pharmacokinetic criteria alongside in-depth safety/toxicity studies. The long-term objective of this STTR is to develop novel, targeted, safe and potent inhibitors of the STARS-SRF pathway that may become drug candidates for IND-enabling studies.