Optimisation and mechanistic characterization of a selective benzoxazine-based MAP4K4 inhibitor in pancreatic cancer cells

values of 4.41-4.65 μM and 4.03-5.12 μM, respectively. F389-0736 also inhibited clonogenic growth and induced sub-G1 accumulation with activation of apoptotic signalling. RNA sequencing identified 398 differentially expressed genes and revealed enrichment of inflammatory and stress response pathways, programmed cell death programs, oncogenic signalling perturbation, and metabolic reprogramming. These findings identify F389-0736 as a potent and selective benzoxazine-based MAP4K4 inhibitor and support its use as a chemical probe and lead scaffold for investigating MAP4K4-dependent signalling and therapeutic vulnerability in pancreatic cancer.