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

Abstract Hypoxia inducible factor‐1 α (HIF‐1 α ) 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‐1 α 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 F 1 ‐ATP synthase, ATP5B, is identified as the binding protein of HI‐derivatives. Mechanistically, HI‐101 promotes the binding of HIF‐1 α mRNA to ATP5B, thus inhibiting HIF‐1 α 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 IC 50 of 26 n m . The findings provide a new strategy for further developing HIF‐1 α inhibitors by translational inhibition through ATP5B.