azacitidine + venetoclax + APL-4098

Azacitidine + venetoclax + APL-4098 is a combination therapy being developed by Apollo Therapeutics for the treatment of myeloid malignancies. The novel component, APL-4098, is a potent, selective, ATP-competitive small-molecule inhibitor of general control nonderepressible 2 (GCN2) kinase. GCN2 is a key sensor in the integrated stress response (ISR) pathway that regulates protein synthesis in response to amino acid deprivation. By inhibiting GCN2, APL-4098 disrupts mitochondrial processes and targets leukemia stem cells. This effect is combined with azacitidine, a hypomethylating agent that inhibits DNA methyltransferase, and venetoclax, a selective BCL-2 inhibitor that restores the apoptotic signaling pathway. The triplet combination is currently being evaluated in Phase 1 clinical trials for patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).