Among numerous posttranslational regulation patterns, phosphorylation is reversibly controlled by the balance of kinases and phosphatases. The major form of cellular signaling involves the reversible phosphorylation of proteins on tyrosine, serine, or threonine residues. However, altered phosphorylation levels are found in diverse diseases, including cancer, making kinases and phosphatases ideal drug targets. In contrast to the success of prosperous kinase inhibitors, design of small molecules targeting phosphatase is struggling due to past bias and difficulty. This is especially true for serine/threonine phosphatases, one of the largest phosphatase families. From this perspective, we aim to provide insights into serine/threonine phosphatases and the small molecules targeting these proteins for drug development, especially in cancer. Through highlighting the modulation strategies, we aim to provide basic principles for the design of small molecules and future perspectives for the application of drugs targeting serine/threonine phosphatases.

No abstract

No 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 FOF1‐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.