Kinase-targeted therapy has been widely used as a lifesaving strategy for cancer patients. However, many patients treated with targeted cancer drugs are clinically observed to rapidly develop acquired resistance. Kinase gatekeeper mutation is one of the most chief factors contributing to the resistance, which modulates the accessibility of kinase’s ATP-binding pocket. Previously, the pan-kinase inhibitor Staurosporine and its analogs (termed as Staralogs) have been reported to exhibit wild-type sparing selectivity for some kinase gatekeeper mutants, such as EGFR T790M, Her2 T798M and cSrc T338M. Here, we describe an integrative approach to systematically profile the molecular response of 15 representative Staralogs to 17 kinase gatekeeper mutations in targeted cancer therapy. With the profile we are able to divide gatekeeper mutations into three classes (i.e. classes I, II and III) and to divide Staralogs into two groups (i.e. groups 1 and 2) using heuristic clustering. The class I and II mutations confer consistent sensitivity and resistance for all Staralogs, respectively, while the class III mutations address divergent effects on different Staralogs. The mutations to Ile residue can generally reduce Staralog affinity by inducing unfavorable steric hindrance, whereas the mutations to Met and Leu residues would improve Staralog affinity by establishing favorable S···π interaction, van der Waals packing and/or hydrophobic contact. The group 1 and 2 Staralogs are primarily determined by carbonyl or hydroxyl substitution state at the position 7 of Staralog core, where points to kinase gatekeeper residue and can thus be directly influenced by gatekeeper mutation.

中文翻译：

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在获得针对性的癌症治疗中，对获得性耐药激酶网守突变的staralog反应的系统分析。

激酶靶向疗法已被广泛用作癌症患者的救生策略。然而，临床观察到许多用靶向癌症药物治疗的患者迅速发展获得性耐药。激酶关守突变是导致耐药性的最主要因素之一，它调节激酶的ATP结合口袋的可及性。以前，据报道，泛激酶抑制剂Staurosporine及其类似物（称为Staralogs）对某些激酶网守突变体（例如EGFR T790M，Her2 T798M和cSrc T338M）表现出野生型的选择性。在这里，我们描述了一种综合方法，可系统地分析15种代表性Staralogs对17种激酶关守突变的分子反应，以靶向治疗癌症。通过配置文件，我们能够使用启发式聚类将网守突变分为三类（即I，II和III类），并将Staralogs分为两组（即1和2组）。I类和II类突变分别为所有Staralog提供一致的敏感性和抗性，而III类突变解决了对不同Staralog的不同影响。Ile残基的突变通常可通过诱导不利的位阻而降低Staralog亲和力，而Met和Leu残基的突变可通过建立有利的S··π相互作用，范德华堆积和/或疏水性接触来提高Staralog亲和力。第1组和第2组Staralogs主要由Staralog核心7位的羰基或羟基取代状态决定，