Preclinical evaluation of CT03: A cardiosafe, first-in-class bifunctional MCL1 degrader for the treatment of hematological malignancies.

Abstract

e15107 Background: MCL1, a crucial member of the Bcl2 family, acts as a key pro-survival factor that prevents apoptosis and drives therapeutic resistance in diverse human cancers. While MCL1 inhibitors have reached clinical stages, their development has been severely hindered by dose-limiting cardiac toxicities, characterized by significant elevations in cardiac troponin. Targeted protein degradation offers a transformative alternative by inducing proteasomal degradation of the target rather than mere inhibition. This approach provides superior selectivity, prolonged pharmacodynamic effects, and a significantly improved safety profile. We report the preclinical characterization of CT-03, a novel bifunctional compound designed to selectively degrade MCL1 for treating hematological malignancies. Methods: Ternary complex formation between CT-03, MCL1, and the recruited E3 ligase was validated using biophysical assays. Biological activity was evaluated across a broad panel of human cancer cell lines and primary cells to assess viability and MCL1 levels via Western blotting. Cardiosafety was specifically examined in human iPSC-derived cardiomyocytes. In vivo efficacy was tested in MV4-11 AML xenograft, both as monotherapy and in combination with venetoclax. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were further evaluated in Cynomolgus macaques. Results: CT03 induced potent proteasomal degradation of MCL1, resulting in apoptosis with low nanomolar pIC₅₀ values (~9) in MV4-11, OPM2, and DMS114 cell lines. Importantly, CT-03 demonstrated a unique cardiosafe profile in human iPSC-derived cardiomyocytes, causing only transient MCL1 reduction. This stands in contrast to MCL1 inhibitors, which triggered a 6–15-fold compensatory upregulation of MCL1 persisting after washout—a mechanism linked to clinical cardiac toxicity. In vivo , CT03 showed robust anti-tumor activity and tumor growth inhibition. When combined with low-dose venetoclax (7.5 mpk), CT03 (5 mpk, 2 days on/5 days off) promoted tumor regression. In non-human primates, the compound exhibited a favorable PK/PD profile with effective MCL1 degradation and no evidence of cardiac toxicity or troponin elevation at exposures significantly exceeding predicted human efficacious doses. Conclusions: CT-03 is a highly potent bifunctional MCL1 degrader that achieves complete target coverage and demonstrates a superior safety margin compared to traditional inhibitors. By reducing MCL1 levels rather than inducing compensatory elevation, CT03 mitigates the risk of cardiac adverse events. These results support the clinical potential of CT03 as a promising therapy for high-risk MDS and R/R AML. The compound is currently undergoing IND/CTA-enabling studies, with a First-in-Human Phase 1 trial planned for 2026 to evaluate CT03 as monotherapy and in combination with venetoclax.