Selective MRTF/SRF-Transcription Inhibitors: Novel Anti-fibrotics for IPF

Prasan Pharmaceutical Consultants, Llc, Ypsilanti MI

Investigators

Abstract

DESCRIPTION (provided by applicant): Prasan Pharmaceutical Consultants, LLC in a licensing agreement with the University of Michigan aims to advance and commercialize proprietary MRTF/SRF-transcription inhibitors for treatment of Idiopathic Pulmonary Fibrosis (IPF). IPF affects a person's ability to breathe and get enough oxygen to vital organs. IPF has no cure or effective treatment and has a mortality rate worse than many cancers, with a median survival of only three years from diagnosis. Development of effective treatment for IPF has been hindered by the idiopathic nature and complex pathogenesis of the disease. Multiple pathways involving various profibrotic mediators are implicated in the progression towards an irreversible, fibrotic end stage disease. While it is unclear as to which one or more of these targets needs to be antagonized in order to slow, halt or reverse the disease process, several targeted approaches that are focused mostly on upstream targets to modulate select signaling pathways are currently being pursued. As such, they may potentially be limited by partial efficacy and safety issues. Considering the recent insights into molecular mechanisms of IPF and consistent with NHLBI's recommendations from workshop on Future Research Directions in Idiopathic Pulmonary Fibrosis, Prasan Pharmaceutical strategy is aimed at targeting Rho signaling through a myocardin-related transcription factor (MRTF) and serum response factor (SRF) mediated gene transcription mechanism. This mechanism - recently shown to represent a final common pathway for many of the current drug targets, has great potential for efficacy - equivalent to blocking multiple upstream pathways. Inhibitors of this pathway discovered at the University of Michigan will be developed by Prasan Pharmaceutical Consultants, LLC. In this SBIR Phase I, we will evaluate a set of 10 chemically diverse, selective and potent MRTF/SRF transcription inhibitors for solubility, metabolic stability and in vivo systemic exposure and bioavailability. Two of the compounds (lead and back-up candidate) with optimal PK profile will be evaluated in a biomarkers-based, in vivo proof-of-concept (POC) efficacy model of transforming growth factor-(TGF-¿)-induced fibrosis in mice. Outcomes measures include ¿-smooth muscle actin (¿-SMA), connective tissue growth factor (CTGF) and MRTF. POC will be assessed based on statistically significant inhibition of biomarkers and / or fibrosis, compared to control. Given successful POC in this Phase I project, a Phase II SBIR application is planned to more extensively develop optimized compounds with full potential for therapeutic application.