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

• 批准号: 10463549
• 负责人: Natasha M. Nesbitt
• 金额: $ 76.4万
• 依托单位: BLOOD CELL TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463549
• 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; base; 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; meetings; mutant; nanomolar; new therapeutic target; novel; novel drug class; pre-clinical; preclinical development; programs; public health relevance; receptor; research and development; small molecule inhibitor; success; thrombotic complications; tool; validation studies; virtual screening

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

项目主任/主要研究者（最后，第一，中间）：NESBITT，娜塔莎M.。 项目总结/摘要 该第二阶段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 一种新型药物靶点的小分子抑制剂，可调节人类血小板的产生。工作范围 建立在强有力的遗传和生物化学证据的基础上，将胆绿素IX的氧化还原依赖性酶活性与 还原酶（BLVRB）在巨核细胞发育的以前未表征的调节途径中的作用， 增强血小板生成。在计算机虚拟筛选与我们的新的评分功能，导致识别 预测约20种化合物抑制BLVRB的氧化还原活性。生物化学和基于细胞的检测方法经过验证 这些化合物中的四种作为酶的有效抑制剂。一个补充的晶体学分析导致了 鉴定了对BLVRB具有增加的效力的另外两种化合物。我们将使用药物 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 和对BLVRB的选择性。这些化合物将使用体外造血测定法进一步表征 并跟踪体内动物研究，以显示与我们目前的热门化合物相比改善的功效。 该项目的长期成功取决于计算化学、血小板、 生物化学、晶体学和药物发现。成功完成本补助金中提出的研究 与一类新的血小板增强化合物的商业开发具有根本的相关性 其功能独立于已知的血小板生成素（TPO）/c-MPL受体轴。化合物开发和 靶向验证提供了一种高度创新策略， 目前临床使用的直接TPO/c-MPL激动剂（例如血小板活化、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用于进一步的临床前开发。 PHS 398/2590（Rev.06/09） 续页格式