Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models

Uncontrolled proliferation and apoptosis evasion are two hallmarks of acute myeloid leukemia (AML), but the molecular mechanisms remain poorly understood. In this study, it is demonstrated that double over-expresser oncoprotein c-Myc anti-apoptotic protein Bcl-2 a critical “genetic overdrive” in AML associated with poor genetic alterations. Double-knockdown c-Myc/ synergistically kills cells vitro vivo. Moreover, novel oral small molecule combination co-targeting WBC100 Venetoclax (VEN) at low doses developed. Importantly, study shows results deep durable remissions AML, its efficacy superior to frontline hypomethylation azacitidine (AZA) mouse models PDX from relapsed or refractory patients. Mechanically, knockdown induces mitochondrial outer membrane permeabilization c-Myc-knockdown impairs mitochondria biogenesis. Co-targeting c-Myc/Bcl-2 reciprocally abrogates over-proliferation resistance via forming hit biogenesis machinery. The findings for first time demonstrate by WBC100/Venetoclax promising convenient therapy support clinical trial.