Inducing Protein Degradation to Overcome Resistance to Kinase Inhibitors
Inducing Protein Degradation to Overcome Resistance to Kinase Inhibitors
复制标题
诱导蛋白质降解以克服对激酶抑制剂的耐药性
DOI：
10.1021/acs.biochem.2c00223
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发表时间：
2023
期刊：
影响因子：
2.9
通讯作者：
Naito Mikihiko
中科院分区：
文献类型：
--
作者：
Sato Waka;Naito Mikihiko
致癌激酶在癌细胞的异常生长中起重要作用。因此，小分子选择性抑制致癌激酶是抑制癌细胞生长的有力策略。到目前为止，超过60种激酶抑制剂已被批准用于临床，并有助于延长癌症患者的寿命，包括那些患有慢性骨髓性白血病、非小细胞肺癌和恶性黑色素瘤的患者。然而，癌细胞经常对激酶抑制剂产生耐药性，从而导致癌症治疗失败。耐药的主要机制是激酶结构域的突变，它阻碍了激酶抑制剂与靶激酶的结合。为了克服耐药性，可以抑制耐药激酶的新型抑制剂逐渐被开发出来，但不可避免的是，癌细胞将再次获得对这些新型抑制剂的耐药性。近年来，利用嵌合小分子如PROTACs和SNIPERs诱导靶向蛋白降解技术（以下统称PROTACs）得到了发展，并作为一种新的药物开发模式受到了广泛关注。PROTAC构成靶蛋白的配体，与E3泛素连接酶的另一个配体连接。在细胞中，PROTAC招募E3泛素连接酶到靶蛋白上，从而诱导靶蛋白的泛素化和蛋白酶体降解（图1a）。在结合各种激酶抑制剂后，已经开发出许多降解致癌激酶的PROTACs，包括针对BCR-ABL融合激酶、ALK融合激酶、EGF受体酪氨酸激酶和布鲁顿酪氨酸激酶的PROTACs。在药理学上，这些PROTACs比激酶抑制剂有优势，包括更好的选择性和更持久的激酶活性抑制，即使在药物去除后。然而，这些protac中的大多数不能降解对激酶抑制剂具有抗性的激酶，因为它们使用不能与抗性激酶结合的常规激酶抑制剂作为靶配体。为了诱导耐药致癌激酶的降解，有几种可能的方法。
Oncogenic kinases play important roles in the aberrant growth of cancer cells. Therefore, selective inhibition of oncogenic kinases by small molecules is a powerful strategy for suppressing cancer cell growth. So far, more than 60 kinase inhibitors have been approved for clinical use and have contributed to the extended life span of cancer patients, including those suffering from chronic myelogenous leukemia, non-small cell lung cancers, and malignant melanomas. However, cancer cells often develop resistance to kinase inhibitors, which results in the failure of cancer therapy. Major mechanisms of drug resistance are mutations in the kinase domain, which hampers the binding of kinase inhibitors to the target kinases. To overcome the resistance, novel inhibitors that can inhibit resistant kinases are progressively developed, but it is inevitable that cancer cells will acquire resistance again to these novel inhibitors.Technologies for inducing targeted protein degradation by chimeric small molecules such as PROTACs and SNIPERs (hereafter collectively called PROTACs) have been developed recently and attracted attention as a novel modality for drug development. 1 A PROTAC constitutes a ligand for a target protein linked to another ligand for an E3 ubiquitin ligase. In the cells, a PROTAC recruits an E3 ubiquitin ligase to the target protein, thereby inducing ubiquitylation and proteasomal degradation of the target (Figure 1 a). Upon incorporation of various kinase inhibitors, a number of PROTACs that degrade oncogenic kinases have been developed, including those against BCR-ABL fusion kinase, ALK fusion kinase, EGF receptor tyrosine kinase, and Bruton’s tyrosine kinase. Pharmacologically, these PROTACs showed advantages over kinase inhibitors, which include better selectivity and longerlasting suppression of kinase activity even after drug removal. However, most of these PROTACs could not degrade kinases that are resistant to kinase inhibitors, because they used conventional kinase inhibitors that cannot bind to the resistant kinases as target ligands. 2 To induce degradation of the resistant oncogenic kinases, a couple of approaches are possible.