一种心脏安全的首创（first-in-class）MCL-1降解剂用于治疗血液系统恶性肿瘤的临床前评估

MCL-1, a member of the Bcl-2 family of apoptosis regulators, is a critical pro-survival factor implicated in tumor maintenance and therapeutic resistance across a wide range of cancers. Although several MCL-1 inhibitors have entered clinical development, many were discontinued due to dose-limiting cardiac toxicity. Targeted protein degradation offers an alternative strategy with potential advantages, including improved selectivity, prolonged pharmacodynamic effects, and reduced risk of adverse cardiac events. Here, we describe the discovery and preclinical characterization of a novel bifunctional compound designed to selectively degrade MCL-1 for the treatment of hematological malignancies. Biophysical assays confirmed ternary complex formation between the degrader, MCL-1, and an E3 ligase. The compound induces proteasome-dependent degradation of MCL-1, leading to apoptosis and cell death in a broad panel of human cancer cell lines, with low nanomolar potency (pIC₅₀ ~9 for MV4-11, OPM-2, and DMS114). Cytotoxic effects were observed across leukemia, lung cancer, and multiple myeloma models, while sparing normal and primary cells. In human iPSC-derived cardiomyocytes, the degrader caused only transient reduction of MCL-1 levels, in contrast to MCL-1 inhibitors that induced 6-15-fold MCL-1 upregulation persisting after washout, a mechanism linked to elevated cardiac troponin in clinical trials. In vivo , the compound demonstrated strong antitumor activity in AML xenograft models, inducing MCL-1 degradation and tumor growth inhibition. Combination with low-dose venetoclax (7.5 mpk) promoted tumor regression at 5 mpk using an intermittent dosing regimen (2 days on/5 days off). In non-human primates, the compound exhibited a favorable pharmacokinetic/pharmacodynamic profile with effective MCL-1 degradation and no evidence of cardiac toxicity at exposures exceeding predicted human efficacious levels. In conclusion, we have developed a highly potent and selective bifunctional MCL-1 degrader that shows robust activity in vitro and in vivo , complete target coverage, and a favorable safety margin compared with MCL-1 inhibitors. These findings support MCL-1 degradation as a promising therapeutic approach for hematologic malignancies. The compound is advancing through IND/CTA-enabling studies, with a first-in-human Phase 1 trial planned for 2026.