MCL1 基因在癌症中经常被扩增，并编码抗凋亡蛋白骨髓细胞白血病 1 (MCL1)，这赋予了对当前护理标准的抵抗力。因此，MCL1是一个有吸引力的抗癌靶点。在这里，我们将 BRD-810 描述为一种有效的选择性 MCL1 抑制剂，其关键设计原理是快速全身清除，以尽可能减少与 MCL1 抑制相关的曲线驱动毒性区域。 BRD-810 在体外 4 小时内诱导快速细胞杀伤，但在同一 4 小时窗口内，即使在超药理学浓度下，对人诱导多能干细胞来源的心肌细胞中的细胞活力或肌钙蛋白 I 释放也没有影响。尽管 BRD-810 在血浆中的停留时间很短，但 BRD-810 在异种移植血液学和实体瘤模型中仍具有体内功效。总的来说，我们的数据支持这样的假设：用 BRD-810 短期抑制 MCL1 可以诱导肿瘤细胞凋亡，同时保持可接受的安全性。因此，我们打算将 BRD-810 推进临床试验。© 2024。作者。

The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.© 2024. The Author(s).