Discovery, preclinical safety, and efficacy characterization of SMAC mimetic S-016-1348 as a potential cancer therapeutic.

Counteracting XIAP (X-linked inhibitor of apoptosis) and IAP by mimicking SMAC (second mitochondria-derived activator of caspase) function is a clinically validated therapeutic option against solid tumors. Antitumor efficacy of currently available SMAC mimetics is limited due to their dependence on TNF-α. Utilizing a medicinal chemistry approach, here, we report the identification and preclinical characterization of the SMAC-mimetic compound S-016-1348, which can even promote cancer cell death independent of TNF-α. Its potent capability to upregulate functional death receptor 5 (DR5) expression is the key differentiator for its monotherapy application against diverse tumor types. S-016-1348 demonstrates marked antitumor efficacy in colon and head and neck cancer and triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) models. S-016-1348 holds drug-like properties for its excellent oral bioavailability across species, promising pharmacokinetic properties, and is well tolerated in preclinical safety evaluations with high safety margins. These findings highlight the translational potential of SMAC-mimetic S-016-1348 as a monotherapy against solid tumors.