Cardio-safe degrader CT-03p degrades MCL-1 and overcomes venetoclax resistance in AML.

Abstract

Abstract BCL-2 family proteins are key cell death regulators. Among them, BCL-2 and MCL-1 are major anti-apoptotic proteins and play critical roles in survival and chemoresistance of malignant cells including acute myeloid leukemia (AML). The FDA-approved BCL-2 inhibitor venetoclax (VEN) and hypomethylation agent combination has greatly improved outcomes in AML but most patients ultimately relapse. MCL-1 is upregulated by multiple cell survival signaling proteins and is known to play a major role in resistance to BCL-2 inhibition. We reported that MCL-1 not only directly protects leukemia cells from death but also exerts other functions that support leukemia growth and survival including regulating metabolic activities and leukemia-stroma interactions (Carter BZ et al., Haematologica 2022). Several MCL-1 inhibitors have been developed and entered clinical trials in AML. However, increased troponin levels, suggesting potential cardiotoxicity in patients treated with MCL-1 inhibitors curtailed their clinical development. Alternative approaches that effectively target this protein are needed. CT-03p is a cereblon-based MCL-1 bifunctional degrader developed by Captor Therapeutics. Unlike MCL-1 inhibitors that increase stability and prevent degradation of MCL-1, which triggers cardiotoxicity, the MCL-1 degrader does not affect non-human primate cardiac function in vivo at doses exceeding Degradation Dose 50 by over 100 times. Cardio-safety has been established by troponin I and D analyses and in the histopathological examination. We found that CT-03p decreased MCL-1 protein levels, induced cell death, and decreased viability in various AML cells. Like MCL-1, which functions as a resistance factor to BCL-2 inhibitor, BCL-2 is a resistance factor to the MCL-1 degrader. CT-03p is highly active in AML cells with acquired resistance to VEN. Importantly, the combination of CT-03p and VEN is highly synergistic in AML cells and stem/progenitor cells resistant to VEN, CPT-098, or both BCL-2 and MCL-1 inhibition. Metabolic analysis shows that CT-03p reduces oxidative phosphorylation and fatty acid oxidation in AML cells, which both contribute to VEN and chemotherapy resistance. Collectively, our data demonstrate that CT-03p degrades MCL1, induces cell death, targets metabolic activities, and overcomes VEN resistance in AML cells. The importance of MCL-1 in AML resistance and the lack of cardiotoxicity of CT-03p warrants future development of this degrader.