Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy.
Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy.
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DOI：
10.1016/j.jbc.2023.104572
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发表时间：
2023-04
影响因子：
4.8
通讯作者：
Wei, Wenyi
中科院分区：
文献类型：
--
作者：
Peng, Yunhua;Liu, Jing;Inuzuka, Hiroyuki;Wei, Wenyi
翻译后修饰(PTM)调节蛋白质功能的方方面面。因此，PTM的上游调节因子，如激酶、乙酰转移酶或甲基转移酶，是包括癌症在内的人类疾病的潜在治疗靶点。到目前为止，这些PTM上游调节因子的多种抑制剂和/或激动剂已在临床使用，而其他的仍在开发中。然而，这些上游调控因子不仅控制与疾病相关的靶蛋白的PTM，还控制其他与疾病无关的底物蛋白。因此，非靶向干扰活动可能会引入不必要的非靶向毒性问题，从而限制这些药物在成功的临床应用中的使用。因此，仅调节疾病相关蛋白靶标的特定PTM的替代药物可能在治疗副作用相对较低的疾病方面提供更精确的效果。为此，最近化学诱导邻近反应已成为一种强有力的研究工具，一些化学邻近诱导因子(CIPS)已被用于靶向和调节蛋白质的泛素化、磷酸化、乙酰化和糖基化。这些CIPS具有很高的转化为临床药物的潜力，几个例子，如PROTACs和MGDS现在正在进行临床试验。因此，需要开发更多的CIPS来涵盖所有类型的PTM，如甲基化和棕榈酰化，从而为基础研究和临床应用提供全方位的工具来调节蛋白PTM，从而有效地治疗癌症。
Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators of PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists of these PTM upstream regulators are in clinical use, while others are still in development. However, these upstream regulators control not only the PTMs of disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted off-target toxicity issues that limit the use of these drugs in successful clinical applications. Therefore, alternative drugs that solely regulate a specific PTM of the disease-relevant protein target may provide a more precise effect in treating disease with relatively low side effects. To this end, chemically induced proximity has recently emerged as a powerful research tool, and several chemical inducers of proximity (CIPs) have been used to target and regulate protein ubiquitination, phosphorylation, acetylation, and glycosylation. These CIPs have a high potential to be translated into clinical drugs and several examples such as PROTACs and MGDs are now in clinical trials. Hence, more CIPs need to be developed to cover all types of PTMs, such as methylation and palmitoylation, thus providing a full spectrum of tools to regulate protein PTM in basic research and also in clinical application for effective cancer treatment.
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