Project Grant R44HL150927

OPTIMIZATION OF BILIVERDIN IX? REDUCTASE REDOX INHIBITORS AS NOVEL REAGENTS FOR ENHANCING PLATELET PRODUCTION - PROGRAM DIRECTOR/PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): NESBITT, NATASHA M.. PROJECT SUMMARY/ABSTRACT THIS PHASE II SBIR PROPOSAL WILL SUPPORT OUR ONGOING DRUG DISCOVERY PROGRAM 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. IN SILICO VIRTUAL SCREENING WITH OUR NOVEL SCORING FUNCTION LED TO THE IDENTIFICATION OF ~20 COMPOUNDS PREDICTED TO INHIBIT THE REDOX ACTIVITY OF BLVRB. BIOCHEMICAL AND CELL-BASED ASSAYS VALIDATED FOUR OF THESE COMPOUNDS AS POTENT INHIBITORS OF THE ENZYME. A COMPLEMENTARY CRYSTALLOGRAPHIC ASSAY LED TO THE IDENTIFICATION OF TWO ADDITIONAL COMPOUNDS WITH INCREASED POTENCY TOWARDS BLVRB. WE WILL EMPLOY MEDICINAL AND COMPUTATIONAL CHEMISTRY TO OPTIMIZE OUR HIT COMPOUNDS TO DEVELOP LEAD COMPOUNDS WITH IMPROVED POTENCY AND SELECTIVITY FOR BLVRB. THESE COMPOUNDS WILL BE FURTHER CHARACTERIZED USING IN VITRO HEMATOPOIETIC ASSAYS AND FOLLOW UP IN VIVO ANIMAL STUDIES TO SHOW IMPROVED EFFICACY IN COMPARISON TO OUR CURRENT HIT COMPOUNDS. LONG-TERM SUCCESS OF THIS PROJECT IS PREDICATED ON SYNERGISTIC EXPERTISE IN COMPUTATIONAL CHEMISTRY, PLATELET BIOCHEMISTRY, CRYSTALLOGRAPHY, AND DRUG DISCOVERY. SUCCESSFUL COMPLETION OF THE RESEARCH PROPOSED IN THIS GRANT 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 PROVIDE A HIGHLY INNOVATIVE STRATEGY THAT WOULD THEORETICALLY BYPASS TOXICITIES ASSOCIATED WITH DIRECT TPO/C-MPL AGONISTS CURRENTLY IN CLINICAL USE (SUCH AS PLATELET ACTIVATION, THROMBOEMBOLIC COMPLICATIONS, AND BONE MARROW FIBROSIS), WHILE GENERATING FIRST-IN-CLASS REDOX INHIBITORS FOR FURTHER PRE-CLINICAL DEVELOPMENT. PHS 398/2590 (REV. 06/09) PAGE CONTINUATION FORMAT PAGE