Targeting LRRC8 signaling to prevent & treat arterial thrombosis in type 2 diabetes

针对 LRRC8 信号传导以防止

• 批准号: 10765748
• 负责人: Jaehyung Cho
• 金额: $ 32.35万
• 依托单位: SENSEION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10765748
• 关键词: Agonist; Antiplatelet Drugs; Aspirin; Biological Availability; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cells; Cerebrum; Cessation of life; Clinical; Clinical Research; Combined Modality Therapy; Complex; Coronary; Cyclic GMP; Data; Diabetes prevention; Diabetic mouse; Direct Costs; Dose; Drug Kinetics; Economic Burden; Ensure; Event; Excretory function; Experimental Genetics; GCG gene; Head; Health; Hemorrhage; Hospitalization; Human; Human Genetics; Human Genome; In Vitro; Integrins; Investigational Drugs; Investigational New Drug Application; Ion Channel; Ischemia; Isoenzymes; Lead; Leucine-Rich Repeat; Marketing; Metabolism; Mission; Mus; Myocardial Infarction; Myocardial Ischemia; National Center for Advancing Translational Sciences; Non-Insulin-Dependent Diabetes Mellitus; Oral; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Proteins; Regulation; Research; Residual state; Series; Signal Transduction; Site; Societies; Solubility; Stroke; Stroke prevention; Testing; Therapeutic; Thrombin Receptor; Thrombosis; Thrombus; Toxic effect; Work; absorption; atherosclerotic plaque rupture; blood glucose regulation; cardiovascular disorder prevention; cardiovascular disorder risk; care costs; cytotoxicity; efficacy study; glycemic control; improved; in vivo; inhibitor; innovation; lead series; manufacture; manufacturing organization; meter; mouse genetics; multiple drug use; non-diabetic; novel; novel therapeutics; pandemic disease; phase 1 study; phase 2 study; phenome; platelet function; pre-clinical; prevent; receptor; response; small molecule; stroke therapy; thrombotic; tool

Project Summary Cardiovascular disease (CVD) including stroke and myocardial infarction (MI), and Type 2 diabetes (T2D) are overlapping global pandemics. CVD is the most common cause of death in patients with T2D and the economic burden of stroke and myocardial ischemia in patients with T2D is staggering. While newer glycemic control agents like SGLT2 inhibitors and GLP1 agonists can help reduce CVD events in T2D, significant residual CVD risk remains. Stroke and MI most often occur when a platelet-rich thrombus form at the site of a ruptured atherosclerotic plaque, occluding the vessel lumen, and resulting in downstream ischemia. There are at least four classes of drugs available to inhibit platelet rich thrombi formation including aspirin, P2Y12 receptor inhibitors, and thrombin receptor inhibitors. While current antiplatelet drugs can reduce CVD events and death, their therapeutic potential is limited by major bleeding. Thus, there is a large unmet clinical and commercial need for a drug that improves glycemic control in T2D and also safely prevents cerebral and coronary vascular thrombosis. Senseion Therapeutics Inc. has been developing novel glycemic control agents derived from a tool compound SN-401 (SN-4XX) targeting LRRC8 proteins. In the course of developing these T2D therapeutics, we discovered human genetic evidence implicating LRRC8 regulation of platelet function in humans. We then validated LRRC8 proteins as a target for antiplatelet activity using targeted mouse genetics, and confirmed both in vitro and in vivo antiplatelet/antithrombotic activity of a novel SN-401 derived compound that also demonstrates glycemic control activity. We propose that SN-4XX compounds represent a first-in-class therapeutic approach with dual glycemic control and antithrombotic activity. We anticipate these drugs to fill a large unmet clinical need to improve glycemic control in T2D and also safely prevent cerebral and coronary vascular thrombosis, reducing the large residual risk of CVD events associated with T2D. Phase 1 AIMS: · AIM 1: Evaluate previously synthesized compounds for in vitro antiplatelet and in vivo antithrombotic activity. · AIM 2: Complete in vitro Absorption, Distribution, Metabolism, Excretion, Toxicity. Phase 2 AIMS: · AIM 1: Perform in vivo oral dosing pharmacokinetics, in vitro ion channel selectivity studies, and in vivo dose range-finding toxicity studies. · AIM 2: Perform pre-clinical SN-4XX dose-response, head-to-head efficacy, combination therapy and reversibility for antithrombotic activity versus bleeding. · AIM 3: Manufacture the lead SN-4XX compound under cGMP conditions required for all IND-enabling studies, at least Phase I clinical studies, and all 24-month stability studies.

项目摘要 心血管疾病（CVD），包括中风和心肌梗塞（MI）和2型糖尿病（T2D） 重叠的全球大流程。 CVD是T2D患者和经济的最常见死亡原因 T2D患者的中风和心肌缺血负担令人震惊。而新的血糖控制 SGLT2抑制剂和GLP1激动剂等代理可以帮助减少T2D中的CVD事件 风险仍然存在。当破裂的部位形成富血小板的血栓形成时，中风和MI通常发生 动脉粥样硬化斑块，阻塞血管腔，导致下游缺血。至少有 可抑制血小板富的血栓形成的四类药物，包括阿司匹林，P2Y12受体抑制剂， 和凝血酶受体抑制剂。尽管当前的抗血小板药物可以减少CVD事件和死亡 治疗潜力受到重度出血的限制。那是很大的未满足的临床和商业需求 用于改善T2D血糖控制并安全防止脑血管的药物 血栓形成。 Vension Therapeutics Inc.一直在开发源自工具的新型血糖控制剂 靶向LRRC8蛋白的化合物SN-401（SN-4XX）。在开发这些T2D疗法的过程中， 我们发现了人类血小板功能的人类遗传证据隐含的LRRC8调节。我们 然后验证LRRC8蛋白作为使用靶向小鼠遗传学的抗血小板活性的靶标，并确认 新型SN-401衍生化合物的体外和体内抗血小板/抗血栓形成活性 证明血糖控制活性。我们建议SN-4XX化合物代表第一类 双重血糖控制和抗血栓形成活性的治疗方法。我们预计这些药物 为了满足大量未满足的临床需求，以改善T2D的血糖控制并安全防止脑 和冠状动脉血栓形成，降低了与T2D相关的CVD事件的巨大残留风险。 第1阶段目的： AIM 1：评估先前合成的体外抗血小板和体内抗血栓形成化合物 活动。 ·目标2：完整的体外吸收，分布，代谢，排泄，毒性。 第2阶段的目的： 目标1：进行体内口服药代动力学，体外离子通道选择性研究和体内 剂量范围调查毒性研究。 AIM 2：执行临床前SN-4XX剂量反应，正面效率，组合疗法和 抗血栓性活动与出血的可逆性。 AIM 3：在所有辅助的CGMP条件下生产铅SN-4XX化合物 研究，至少I期临床研究以及所有24个月的稳定性研究。