Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.

The Bcl-2 inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in elderly patients with acute myeloid leukemia (AML). However, its clinical efficacy is frequently constrained by the emergence of drug resistance, which involves the overexpression or induction of Mcl-1 and Bcl-xL proteins. To address this challenge, we developed a novel strategy to enhance venetoclax activity and overcome resistance by producing NOXA through the conjugation of dihydroartemisinin (DHA) to venetoclax using a chemical synthesis approach. The resulting conjugate, A1, retains potent Bcl-2 inhibitory activity and significantly enhances NOXA production by promoting interactions between the DHA-derived endoperoxide bridge and heme. Mechanistically, A1 effectively overcomes resistance caused by Mcl-1 and Bcl-xL protein through NOXA-mediated Mcl-1 and cyclin D1 protein degradation, respectively. Optimization of the linker design of A1 yielded PEG-linked conjugates with increased in vivo efficacy. This study introduces a new generation of venetoclax-based compounds with dual functionality: enhanced NOXA production and robust degradation of anti-apoptotic and cell-cycle-regulating proteins. Furthermore, we uncover a promising therapeutic strategy to overcome drug resistance in venetoclax-based AML treatments.