Trueline Therapeutics Inc., Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Cancer. 2024 Oct;5(10):1479-1493. doi: 10.1038/s43018-024-00814-0. Epub 2024 Aug 23.
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.
MCL1 基因在癌症中经常被扩增，其编码抗凋亡蛋白髓样细胞白血病 1（MCL1），这使肿瘤对当前的标准治疗产生抵抗。因此，MCL1 是一个有吸引力的抗癌靶点。在这里，我们描述了 BRD-810 作为一种有效的、选择性的 MCL1 抑制剂，以及其快速全身清除的关键设计原理，以潜在地最小化与 MCL1 抑制相关的曲线下面积驱动的毒性。BRD-810 在体外 4 小时内迅速诱导细胞杀伤，但在相同的 4 小时窗口内，对人诱导多能干细胞衍生的心肌细胞的细胞活力或肌钙蛋白 I 释放没有影响，即使在高于药理学浓度的情况下也没有影响。在体内，尽管 BRD-810 在血浆中的半衰期很短，但 BRD-810 仍能在异种移植血液学和实体瘤模型中诱导疗效。总之，我们的数据支持这样一种假设，即 BRD-810 对 MCL1 的短期抑制可以在维持可接受的安全性的情况下诱导肿瘤细胞凋亡。因此，我们打算将 BRD-810 推进到临床试验中。
