Discovery of a Novel HSP90-Targeting Inhibitor for AML from the Marine Aaptamine Scaffold.

Resistance to single-target therapies has spurred interest in multitarget strategies for acute myeloid leukemia (AML). Heat shock protein 90 (HSP90), a chaperone that stabilizes numerous oncogenic client proteins, represents an attractive therapeutic target for AML; however, the clinical development of early HSP90 inhibitors was limited by dose-limiting toxicities and an excessive heat-shock response (HSR). Through structural optimization of the marine aaptamine scaffold and target identification, ap-a48 was identified as a novel HSP90-targeting anti-AML lead that exhibits potent anti-AML activity and acceptable preliminary tolerability while inducing only a modest HSR. In rats, ap-a48 showed favorable pharmacokinetics with 65.3% oral bioavailability, and in HL-60 xenograft mouse models, it suppressed tumor growth (71.2% inhibition at intraperitoneal 40 mg/kg; 67.3% at oral 60 mg/kg) without significant hepatotoxicity or major organ abnormalities. These findings identify ap-a48 as a promising marine-natural-product-derived HSP90-targeting lead for AML therapy.