International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
J Med Chem. 2020 Oct 8;63(19):10726-10741. doi: 10.1021/acs.jmedchem.0c00507. Epub 2020 Jun 2.
Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
临床上对小分子激酶抑制剂（SMKIs）的获得性耐药已成为癌症治疗中一个主要的“未满足的临床需求”。迄今为止，已有六种 SMKIs 通过针对靶标突变引起的获得性耐药而被批准用于癌症患者的治疗。这些主要集中在突变激酶 Bcr-Abl T315I、EGFR T790M 和 ALK L1196M 上。在此，我们总结了在发现这些代表性 SMKIs 中采用的主要药物化学策略，例如避免空间位阻、与突变残基形成额外相互作用以及与活性位点半胱氨酸形成共价键以克服对可逆抑制剂的耐药性。此外，我们还简要描述了变构激酶抑制剂和蛋白水解靶向嵌合体（PROTAC）作为另外两种潜在策略，同时探讨了该领域的未来机遇。
