Optimization of biliverdin IXβ reductase redox inhibitors as novel reagents for enhancing platelet production

优化胆绿素 IXβ 还原酶氧化还原抑制剂作为增强血小板生成的新型试剂

基本信息

批准号：
10641871
负责人：
Natasha M. Nesbitt
金额：
$ 61.32万
依托单位：
BLOOD CELL TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641871
关键词：
Affinity Agonist Alleles Animals Biliverdine Biochemical Biochemistry Biological Assay Biology Blood Cells Blood Platelets Blood coagulation Bone Marrow Businesses Bypass Cells Characteristics Chemicals Cicatrix Clinical Clinical Research Crystallography Data Development Diagnostic Drug Kinetics Drug Targeting Enzyme Inhibitor Drugs Excretory function Exposure to FDA approved Genetic Grant Hematological Disease Hematopoietic Hemorrhage Human In Vitro Interleukin-11 Laboratories Lead Life Link MPL gene Megakaryocytes Metabolic Pathway Metabolism Modeling Mus Myelofibrosis Oxidation-Reduction Oxidoreductase Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phenocopy Phenotype Platelet Activation Platelet Count measurement Platelet Transfusion Preparation Principal Investigator Production Program Development Property Publications Reagent Recovery Regulatory Pathway Research Safety Small Business Innovation Research Grant Stress Structure-Activity Relationship Technology Therapeutic Thrombocytopenia Thrombopoiesis Thrombopoietin Toxic effect Validation Work absorption blood formation chemotherapy computational chemistry cost design drug development drug discovery efficacy evaluation follow-up improved in silico in vivo in vivo evaluation induced pluripotent stem cell inhibitor innovation interleukin-11 receptor lead candidate lead optimization mutant nanomolar new therapeutic target novel novel drug class pharmacologic pre-Investigational New Drug meeting pre-clinical preclinical development programs public health relevance receptor research and development small molecule inhibitor success thrombotic complications tool validation studies virtual screening

项目摘要

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

项目总监/首席研究员（最后，第一，中间）：NESBITT，Natasha M.. 项目概要/摘要该 II 期 SBIR 提案将支持我们正在进行的药物发现计划，旨在开发和验证调节人体血小板生成的新药物靶点的小分子抑制剂。建立在强有力的遗传和生化证据之上，将胆绿素 IX 的氧化还原依赖性酶活性联系起来还原酶（BLVRB）在巨核细胞发育和以前未知的调节途径中的作用使用我们新颖的评分功能增强的计算机虚拟筛选可以识别出血小板。约 20 种化合物预计可抑制 BLVRB 的氧化还原活性，并经过生化和细胞测定验证。其中四种化合物是该酶的有效抑制剂。我们将鉴定出另外两种对 BLVRB 具有增强效力的化合物。和计算化学来优化我们的热门化合物，以开发具有更高效力的先导化合物和 BLVRB 的选择性将使用体外造血测定进一步表征。并跟进体内动物研究，显示与我们目前的热门化合物相比，功效有所改善。该项目的长期成功取决于计算化学、血小板等方面的协同专业知识生物化学、晶体学和药物发现成功完成了这笔资助中提出的研究。与新型血小板增强化合物的商业开发具有根本相关性独立于已知的血小板生成素 (TPO)/c-MPL 受体轴发挥作用。目标验证提供了一种高度创新的策略，理论上可以绕过与目前临床上使用的直接TPO/c-MPL激动剂（如血小板活化、血栓栓塞并发症、和骨髓纤维化），同时产生一流的氧化还原抑制剂以用于进一步的临床前开发。 PHS 398/2590（修订版 06/09）页码延续格式页