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.

中文翻译：

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通过邻近诱导方式调节磷酸化用于癌症治疗


蛋白质的异常磷酸化会导致各种疾病，尤其是癌症。因此，开发用于精确调节蛋白质磷酸化的小分子在药物设计方面具有巨大的潜力。虽然传统的激酶/磷酸酶小分子调节剂已经显示出一些成功，但事实证明，实现精确的磷酸化调节具有挑战性。异双功能分子的出现，例如磷酸化诱导嵌合小分子 （PHICS） 和磷酸酶募集嵌合体 （PHORC），具有邻近诱导方式，有望通过特异性募集激酶或磷酸酶到目标蛋白质来带来突破。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节的异双功能分子案例，我们重点介绍了这些分子的当前设计策略和特征。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节的异双功能分子药物的现有挑战和未来的研究方向。