6202 – Inhibitors of Rho/MRTF/SRF Gene Transcription

Fibrosis underlies many common chronic diseases as well as several orphan diseases such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). The team behind FibrosIX LLC has developed a novel compound, CCG-257081, that has shown efficacy in preventing fibrosis in several mouse and one rabbit models. A molecular target of this compound was recently found to be pirin, which is a nuclear protein co-transcription factor associated with NFkB, a crucial mediator of inflammation. Our data implicate pirin in regulation of the pro-fibrotic myocardin-related transcription factor (MRTF)/serum response factor (SRF) gene transcription pathway. The MRTF/SRF gene transcription pathway is a critical step in the fibroblast-to-myofibroblast transition that occurs in fibrosis development. This unique dual mechanism means that our compound can inhibit both inflammatory (NFkB) and pro-fibrotic (MRTF) effects of bleomycin toxicit As a primary clinical indication with a low bar to Phase I clinical trials, prevention or reversal of bleomycin-induced pulmonary fibrosis in chemotherapy patients is the target of our SBIR grant. About 10-12% of bleomycin-treated patients develop pneumonitis with progression to pulmonary fibrosis during therapy as a direct result of bleomycin. An estimated 10-20% of these cases are fatal. Thus makes bleomycin-induced lung fibrosis a significant treatment-limiting side effect that impedes the ability of patients with Hodgkin’s disease and germ cell tumors to complete therapy. The goal of our current Phase I SBIR is to test the hypothesis that targeting this dual mechanism with CCG-257081 can prevent lung fibrosis in mouse models that mimic bleomycin chemotherapy. Our ultimate goal is to incorporate CCG-257081 as a standard component of all bleomycin-containing chemotherapy regimens to allow oncologists to treat patients with the full course of bleomycin treatment, resulting in reduced mortality and improved patient outcomes. We have recently submitted a second Phase I SBIR targeted at radiation-induced lung fibrosis. Clinical approval of this compound – or more advanced analogs – would open the door to more expeditious development for more challenging indication such as SSc or IPF. Ed Pagani edpagani@umich.edu 734-763-3558

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