Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.

通过干扰心肌细胞死亡机制来减少梗塞面积（IS）仍然是一个难以实现的目标。 DMX-5804 是应激激活激酶 MAP4K4 的选择性抑制剂，可抑制小鼠心肌梗塞 (MI)、人类多能干细胞衍生的心肌细胞 (hPSC-CM) 和 3D 人类工程心脏组织中的细胞死亡，其忠实于人类希望生物学能够加强临床成功的途径。在这里，DMX-10001 是 DMX-5804 的一种可溶性、快速裂解的前药，被开发用于大型哺乳动物 MI 的静脉注射测试。药效学研究之后，在接受 LAD 球囊闭塞（60 分钟）和再灌注（24 小时）的猪中进行了一项随机、盲法功效研究。登记了三十六只动物； 12 名患者因预先定义的标准、输注前死亡或技术问题而被排除。再灌注前 20 分钟开始 DMX-10001（30 分钟，60 mg/kg/h；23.5 小时，17 mg/kg/h）。在所有测试时间中，从开始输注后 30 分钟开始，DMX-5804 浓度超过口服 DMX-5804 本身后拯救 hPSC-CM 并降低小鼠 IS 水平的五倍以上。尽管 DMX-10001 将 IS（以克或 LV 质量百分比表示）降低了 27%，但 IS 没有显着降低，也没有针对缺血风险区域进行校正的无复流。总之，DMX-5804 的快速裂解前药未能降低大型哺乳动物 MI 中的 IS，尽管超过了在小鼠和 hPSC-CM 中已证明成功的浓度。