International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College 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.
Angew Chem Int Ed Engl. 2020 Aug 10;59(33):13764-13776. doi: 10.1002/anie.201914525. Epub 2020 Apr 1.
Drugs that function through allosteric inhibition of kinase signaling represent a promising approach for the targeted discovery of therapeutics. The majority of developed allosteric kinase inhibitors are characterized as type III and IV inhibitors that show good kinome selectivity but generally lack the subtype selectivity of same kinase family. Recently allosteric inhibitors have been developed that bind outside the catalytic kinase domain with high selectivity for specific kinase subtypes. Allosteric inhibitors that bind to the pseudokinase domain of pseudokinase or the extracellular domain of receptor tyrosine kinases are reviewed. We also review recent developments in the field of allosteric kinase inhibitors including examples of proteolysis targeting chimeras, and highlight the unique binding modes for each type of inhibitors and address future opportunities in this area.
通过变构抑制激酶信号传导起作用的药物代表了靶向发现治疗药物的一种很有前途的方法。大多数已开发的变构激酶抑制剂的特征为 III 型和 IV 型抑制剂，它们表现出良好的激酶组选择性，但通常缺乏同一激酶家族的亚型选择性。最近已经开发出了变构抑制剂，它们与催化激酶结构域外的结合具有针对特定激酶亚型的高选择性。本文综述了与假激酶或受体酪氨酸激酶的细胞外结构域结合的变构抑制剂。我们还综述了变构激酶抑制剂领域的最新进展，包括蛋白酶体靶向嵌合体的实例，并强调了每种类型抑制剂的独特结合模式，并探讨了该领域的未来机遇。
