Development of a biliverdin IX Beta reductase redox inhibitor for enhanced platelet production

Blood Cell Technologies, Llc, Stony Brook NY

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Abstract

? DESCRIPTION (provided by applicant): This Phase I SBIR proposal is the initial step of a critical path initiative designed to develop and validate small molecule inhibitors of a novel drug target regulating platelet production in humans. The scope of work builds on strong genetic and biochemical evidence linking redox-dependent enzymatic activity of biliverdin IX reductase (BLVRB) in a previously-uncharacterized regulatory pathway of megakaryocyte development and enhanced platelet production. Preliminary data applying virtual computational modeling of the BLVRB crystal structure have identified ten compounds predicted to inhibit ligand binding and redox coupling, observations that will be iteratively refined in two synergistic aims designed to identify lead compounds retaining enzymatic inhibitory functions using stringent biochemical and confirmatory cell-based assays (target validation). Long- term success is predicated on synergistic expertise in platelet biochemistry and drug development that will logically extend into Phase II SBIR compound optimization and in vitro characterization. Successful completion of the research has fundamental relevance to commercial development of a new class of platelet- enhancing compounds functioning independently of the known thrombopoietin (TPO)/c-MPL receptor axis. Compound development and target validation using BLVRB redox inhibitors would represent a highly innovative strategy that would theoretically bypass associated toxicities associated with direct TPO/c-MPL agonists currently in clinical studies such as platelet activation, thromboembolic complications, and bone marrow fibrosis.