Zhang Qiuyue, Yu Jia, You Qidong, Wang Lei
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2024 Dec 26;67(24):21695-21716. doi: 10.1021/acs.jmedchem.4c02624. Epub 2024 Dec 9.
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.
蛋白质的异常磷酸化可导致多种疾病，尤其是癌症。因此，开发用于精确调控蛋白质磷酸化的小分子在药物设计方面具有巨大潜力。虽然传统的激酶/磷酸酶小分子调节剂已取得一些成功，但实现精确的磷酸化调控已被证明具有挑战性。具有邻近诱导模式的异双功能分子的出现，如磷酸化诱导嵌合小分子（PHICSs）和磷酸酶募集嵌合体（PHORCs），有望通过特异性地将激酶或磷酸酶募集到目标蛋白质上而带来突破。在此，我们总结了癌症中磷酸化异常的药物靶点，并强调了在癌症治疗中纠正磷酸化的潜力。通过报道的靶向磷酸化调控的异双功能分子案例，我们突出了这些分子当前的设计策略和特点。我们还系统阐述了异常磷酸化靶点与癌症之间的联系，以及开发用于磷酸化调控的异双功能分子药物的现有挑战和未来研究方向。
