Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy.

Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.