School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
J Med Chem. 2022 Jan 13;65(1):58-83. doi: 10.1021/acs.jmedchem.1c01719. Epub 2021 Dec 28.
Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which have the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics of CKIs and discovery of additional irreversible and reversible-covalent cysteine-targeted warheads has inspired the development of this area. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative CKIs, which are categorized by the location of the target cysteine within seven main regions of the kinase: the front region, the glycine rich loop (P-loop), the hinge region, the DFG region, the activation loop (A-loop), the catalytic loop (C-loop), and the remote loop. The emphasis is placed on the design and optimization strategies of CKIs that are generated by addition of a warhead to a reversible lead/inhibitor scaffold. In addition, we address the challenges facing this area of drug discovery.
小分子共价激酶抑制剂 (CKIs) 在药物发现中进入了一个新时代，它们具有持续抑制靶标和高选择性的优势。对 CKIs 结合动力学的深入了解和对额外不可逆和可逆共价半胱氨酸靶向弹头的发现，激发了这一领域的发展。在此，我们总结了在发现这些代表性 CKIs 时采用的主要药物化学策略，这些策略按激酶的七个主要区域内靶半胱氨酸的位置进行分类：前区、甘氨酸丰富环 (P 环)、铰链区、DFG 区、激活环 (A 环)、催化环 (C 环)和远程环。重点是通过在可逆先导物/抑制剂支架上添加弹头来设计和优化 CKIs 的策略。此外，我们还讨论了该药物发现领域面临的挑战。
