Integrated Drug Discovery Center, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, Karnataka, India.
Department of Pharmaceutical Sciences, College of Pharmaceutical Sciences, Dayananda Sagar University, Bengaluru, Karnataka, India.
Chem Biodivers. 2023 Sep;20(9):e202300515. doi: 10.1002/cbdv.202300515. Epub 2023 Sep 1.
The physiological Src proto-oncogene is a protein tyrosine kinase receptor that served as the essential signaling pathway in different types of cancer. Src kinase receptor is divided into different domains: a unique domain, an SH3 domain, an SH2 domain, a protein tyrosine kinase domain, and a regulatory tail, which runs from the N-terminus to the C-terminus. Src kinase inhibitors bind in the kinase domain and are activated by phosphorylation. The etiology of cancer involved various signaling pathways and Src signaling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19 century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. The Src kinase regulated through different kinase pathways (MAPK, PI3K/Akt/mTOR, JAK/STAT3, Hippo kinase, PEAK1, and Rho/ROCK pathways) and proceeded downstream signaling to conduct cell proliferation, angiogenesis, migration, invasion, and metastasis of cancer cells. There are numerous FDA-approved drugs flooded the market but still, there is a huge demand for the creation of novel anticancer drugs. As the existing drugs are accompanied by several adverse effects and drug resistance due to rapid mutation in proteins. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure-activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors.
生理 Src 原癌基因是一种蛋白酪氨酸激酶受体，它是不同类型癌症的重要信号通路。Src 激酶受体分为不同的结构域：独特结构域、SH3 结构域、SH2 结构域、蛋白酪氨酸激酶结构域和从 N 端到 C 端延伸的调节尾部。Src 激酶抑制剂结合在激酶结构域中，并通过磷酸化激活。癌症的病因涉及各种信号通路，Src 信号通路也参与其中。尽管 Src 激酶的失调导致癌症在 19 世纪末被发现，但它仍然被认为是一种 cult 途径，因为它没有被不同的药物化学家或肿瘤学家广泛探索。Src 激酶通过不同的激酶途径（MAPK、PI3K/Akt/mTOR、JAK/STAT3、Hippo 激酶、PEAK1 和 Rho/ROCK 途径）调节，并进行下游信号转导，以促进癌细胞的增殖、血管生成、迁移、侵袭和转移。有许多获得美国食品和药物管理局批准的药物充斥市场，但仍然需要开发新的抗癌药物。由于蛋白质的快速突变，现有药物伴随着许多不良反应和耐药性。在这篇综述中，我们详细阐述了 Src 激酶的结构和激活，以及 Src 激酶抑制剂的开发。我们的小组还提供了过去二十年中 Src 抑制剂的全面概述，包括它们的生物学活性、构效关系和 Src 激酶选择性。我们详细研究了 Src 结合口袋，以更好地理解 Src 抑制剂与氨基酸残基的相互作用。我们通过对顶级化合物的分子对接和 ADMET 研究，为文献提供了有力支持。我们希望当前的分析将成为研究人员的有用资源，并为设计和开发更特异、更选择性和更有效的 Src 激酶抑制剂提供方向。
