Adamantaniline Derivatives Target ATP5B to Inhibit Translation of Hypoxia Inducible Factor-1α

Hypoxia inducible factor-1α (HIF-1α) plays a critical role in cellular adaptation to hypoxia and it is a potential therapeutic target for anti-cancer drugs. Applying high-throughput screening, here it is found that HI-101, a small molecule containing an adamantaniline moiety, effectively reduces HIF-1α protein expression. With the compound as a hit, a probe (HI-102) is developed for target identification by affinity-based protein profiling. The catalytic β subunit of mitochondrial F_O F₁ -ATP synthase, ATP5B, is identified as the binding protein of HI-derivatives. Mechanistically, HI-101 promotes the binding of HIF-1α mRNA to ATP5B, thus inhibiting HIF-1α translation and the following transcriptional activity. Further modifications of HI-101 lead to HI-104, a compound with good pharmacokinetic properties, exhibiting antitumor activity in MHCC97-L mice xenograft model, and HI-105, the most potent compound with an IC₅₀ of 26 nm. The findings provide a new strategy for further developing HIF-1α inhibitors by translational inhibition through ATP5B.