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

The B-cell lymphoma protein 2 (Bcl-2) inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in older 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 the myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma-extra large (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 produced conjugate, A1, retained potent Bcl-2 inhibitory activity and significantly enhanced 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 polyethylene glycol (PEG)-linked conjugates with increased in vivo efficacy. This study introduced a new generation of venetoclax-based compounds with dual functionality, specifically enhanced NOXA production and robust degradation of antiapoptotic and cell cycle-regulating proteins. Furthermore, we uncovered a promising therapeutic strategy to overcome drug resistance in venetoclax-based AML treatments.