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

Abstract 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_OF₁‐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.