Leveraging Structural Diversity and Allosteric Regulatory Mechanisms of Protein Kinases in the Discovery of Small Molecule Inhibitors.
Leveraging Structural Diversity and Allosteric Regulatory Mechanisms of Protein Kinases in the Discovery of Small Molecule Inhibitors.
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利用蛋白激酶的结构多样性和变构调节机制来发现小分子抑制剂。
DOI：
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发表时间：
2018
影响因子：
4.1
通讯作者：
Gennady M Verkhivker
中科院分区：
文献类型：
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作者：
Gennady M Verkhivker
蛋白激酶是一种多功能的分子开关，在信号转导网络中控制功能过程，调节细胞周期和生物体发育的基本生物学过程。生物信息的不断增长和蛋白激酶基因的结构，遗传和药理学研究的显着呼吸显着推进我们的激酶激活，药物结合和变构机制的激酶调节和信号级联反应中的相互作用的知识。与抑制剂结合的蛋白激酶的遗传和分子决定簇的结构和生物化学研究已经成为临床肿瘤学中药物发现努力的基石，从而导致有效抗癌疗法的扩散。在理解蛋白激酶的变构调节方面的最新进展推动了前所未有的努力，旨在发现靶向和变构激酶抑制剂，这些抑制剂可以对抗癌症突变体，并且处于肿瘤学精准医学倡议的最前沿。尽管激酶功能的调节方案多种多样，但二聚化驱动的活化是许多蛋白激酶家族共有的变构调节的常见机制，最值得注意的是在生长因子信号传导和人类疾病中发挥核心作用的ErbB和BRAF激酶。在这篇综述中，我们集中在ErbB和BRAF激酶的结构，生物化学和计算研究，并讨论如何利用这些激酶基因的结构景观的多样性和二聚化依赖的调节机制，可以在激酶抑制剂和激酶活化的变构调节剂的设计和发现。从这项分析中获得的经验教训可以为发现特定的靶向治疗和强大的癌症治疗药物组合提供信息。
Protein kinases are versatile molecule switches that govern functional processes in signal transduction networks and regulate fundamental biological processes of cell cycle and organism development. The continuous growth of biological information and a remarkable breath of structural, genetic, and pharmacological studies on protein kinase genes have significantly advanced our knowledge of the kinase activation, drug binding and allosteric mechanisms underlying kinase regulation and interactions in signaling cascades.. Structural and biochemical studies of the genetic and molecular determinants of protein kinases binding with inhibitors have been the cornerstone of drug discovery efforts in clinical oncology leading to proliferation of effective anticancer therapies. Recent advances in understanding allosteric regulation of protein kinases have fueled unprecedented efforts aiming in the discovery of targeted and allosteric kinase inhibitors that can combat cancer mutants and are at the forefront of the precision medicine initiative in oncology. Despite diversity of regulatory scenarios underlying kinase functions, dimerization-driven activation is a common mechanism of allosteric regulation that is shared by many protein kinase families, most notably ErbB and BRAF kinases that play a central role in growth factor signaling and human disease. In this review, we focused on structural, biochemical and computational studies of the ErbB and BRAF kinases and discuss how diversity of the structural landscape for these kinase genes and dimerization- dependent mechanisms of their regulation can be leveraged in the design and discovery of kinase inhibitors and allosteric modulators of kinase activation. The lessons from this analysis could inform discovery of specific targeted therapies and robust drug combinations for cancer treatment.