Development of Second Generation BLVRB Inhibitors for Treating Chemotherapy Induced Thrombocytopenia

PROJECT SUMMARY Chemotherapy-induced thrombocytopenia (CIT) is one of the main dose-limiting toxicities of myelosuppressive chemotherapy. Indeed, it is estimated that nearly 50% of chemotherapy patients with hematologic malignancies and 33% with solid tumors develop CIT, with the likelihood of developing CIT being somewhat linked to the treatment regimen and/or patient outcomes. Because proper platelet counts are essential for preventing bleeding disorders, which may be fatal, physicians/healthcare providers must take measures to prevent/control CIT. Currently, there is no FDA-approved therapeutic marketed for treating CIT. Previously, a redox defective mutation in the gene BLVRB, which encodes biliverdin IXβ reductase, was identified in a cohort of patients with thrombocytosis. Blood Cell Technologies, LLC has developed a first-generation BLVRB inhibitor that produced a statistically significant increase in platelet numbers in mice with CIT, providing the first evidence for target validation that phenocopies BLVRB-null mice. In this Fast-Track SBIR, we will develop second-generation compounds, aiming to identify a lead-optimized (LO) small molecule inhibitor that will enhance the therapeutic potential of our drug discovery program. This will be accomplished by 1) using in silico modeling to optimize the potency and drug-like properties of the lead first-generation compound, 2) determining the therapeutic range of the LO compound in a mouse model of CIT, 3) determining metabolites of the LO compound, 4) establishing the LO compound’s pharmacokinetic profile, 5) conducting safety studies to determine its therapeutic index, and 6) comparing its efficacy to thrombopoietin (TPO) and FDA-approved TPO receptor agonist (RA) in a mouse model of CIT. The completion of the proposed work will extend to IND-enabling GLP toxicology studies and scale-up production of the compound under current Good Manufacturing Practices (cGMP) to generate clinical trial material to enable first-in-human clinical trials (beyond the scope of this proposal). Funding the development of a potent, safe, and effective BLVRB inhibitor will play a key role in improving outcomes in patients who rely on chemotherapy.