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

项目摘要 心血管疾病（CVD），包括中风和心肌梗死（MI），以及2型糖尿病（T2 D）， 重叠的全球流行病。CVD是T2 D患者最常见的死亡原因， T2 D患者的中风和心肌缺血负担是惊人的。虽然新的血糖控制 SGLT 2抑制剂和GLP 1激动剂等药物有助于减少T2 D患者的CVD事件， 风险依然存在。中风和心肌梗死最常发生在破裂部位形成富含血小板的血栓时， 动脉粥样硬化斑块，阻塞血管腔，并导致下游缺血。至少有 可用于抑制富含血小板血栓形成的四类药物，包括阿司匹林、P2 Y12受体抑制剂， 和凝血酶受体抑制剂。虽然目前的抗血小板药物可以减少心血管事件和死亡， 治疗潜力受到大出血的限制。因此，存在大量未满足的临床和商业需求 用于改善T2 D血糖控制并安全预防脑血管和冠状动脉血管疾病的药物 血栓形成Senseion Therapeutics Inc.一直在开发新的血糖控制剂， 靶向LRRC 8蛋白的化合物SN-401（SN-4XX）。在开发这些T2 D疗法的过程中， 我们发现了人类遗传学证据，表明LRRC 8对人类血小板功能的调节。我们 然后使用靶向小鼠遗传学验证LRRC 8蛋白作为抗血小板活性的靶点，并证实 一种新的SN-401衍生化合物的体外和体内抗血小板/抗血栓形成活性， 显示血糖控制活性。我们认为SN-4XX化合物代表了一流的 具有双重血糖控制和抗血栓活性的治疗方法。我们预计这些药物 以满足改善T2 D血糖控制并安全预防脑卒中的大量未满足的临床需求， 和冠状动脉血栓形成，降低与T2 D相关的CVD事件的大的剩余风险。 第1阶段目标： ·目的1：评价先前合成的化合物用于体外抗血小板和体内抗血栓形成 活动 ·目的2：完成体外吸收、分布、代谢、排泄、毒性。 第2阶段目标： ·目的1：进行体内口服给药代动力学、体外离子通道选择性研究和体内代谢动力学研究。 剂量范围探索毒性研究。 ·目的2：进行临床前SN-4XX剂量反应、头对头功效、组合疗法和 抗血栓活性与出血的可逆性。 ·目标3：在所有IND实现所需的cGMP条件下制造SN-4XX先导化合物 研究，至少I期临床研究和所有24个月稳定性研究。

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.