Identification of small molecule GPVI inhibitors as anti-platelet agents for the treatment of thrombosis with minimal bleeding risk

鉴定小分子 GPVI 抑制剂作为抗血小板药物，用于治疗血栓形成且出血风险最小

• 批准号: MR/Y50340X/1
• 负责人: Richard Foster
• 金额: $ 30.08万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY50340X%2F1
• 关键词: Identification; small; molecule; GPVI; inhibitors

Current treatments for patients who have a risk of arterial thrombosis suffer from sub-optimal efficacy and carry a significant increase in the risk of bleeding. The objective of this proposal is to discover compounds which block a platelet surface receptor, platelet glycoprotein VI (GPVI), which is involved in thrombosis, and for which there is good evidence that inhibition will prove effective without increase the risk of bleeding. This will allow patients to be treated more safely and enable safe dose escalation in high-risk patients, unlike current medicines that have a narrower therapeutic index between efficacy and risk of bleeding. Patients will also have the potential to be co-administered with an anticoagulant agent to further improve efficacy (a scenario that is currently limited due to the bleeding risks associated with the agents used). The eventual aim of the programme is to produce an orally administered once-or-twice daily treatment.The team at the University of Leeds have identified a series of small molecule inhibitors of GPVI which demonstrate evidence of binding at GPVI and efficacy in platelet activation and aggregation assays, as well as a global thrombosis assay performed under flow conditions. The work plan proposed within this application is aimed at optimising the hits for improvement in efficacy, binding affinity and 'drug-like' properties. Additionally, we aim to generate a high-resolution ligand-protein bound crystal structure of a leading inhibitor to further support optimisation of the compound series.The deliverable of the award will be a lead series of compounds possessing robust structure activity relationships, and suitable potency and 'drug-like' properties consistent with a profile ready to attract follow-on investment and further development.

目前对有动脉血栓形成风险的患者的治疗效果不佳，出血风险显着增加。这项建议的目的是寻找能够阻断与血栓形成有关的血小板表面受体--血小板膜糖蛋白VI(GPVI)的化合物，并且有充分的证据表明，对这种化合物的抑制将被证明是有效的，而不会增加出血风险。这将使患者得到更安全的治疗，并使高危患者的安全剂量增加，而不像目前的药物那样，疗效和出血风险之间的治疗指数较窄。患者还有可能与抗凝剂联合给药，以进一步提高疗效(由于与所用药物相关的出血风险，目前这种情况有限)。该计划的最终目标是产生一种每天口服一到两次的治疗方法。利兹大学的研究小组已经确定了一系列GPVI的小分子抑制剂，这些药物证明了GPVI与GPVI结合的证据，以及在血小板激活和聚集分析中的有效性，以及在流动条件下进行的全球血栓形成测试。本申请中提出的工作计划旨在优化HITS，以提高疗效、结合亲和力和类似药物的特性。此外，我们的目标是产生一种领先抑制剂的高分辨率配体-蛋白质结合的晶体结构，以进一步支持化合物系列的优化。该奖项将交付一系列领先的化合物，这些化合物具有强大的结构活性关系，以及与准备吸引后续投资和进一步开发的轮廓一致的适当效力和类似药物的特性。