Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance
Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance
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DOI：
10.1021/acs.jmedchem.2c00030
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发表时间：
2022-06-09
影响因子：
7.3
通讯作者：
Shi，Zhi-Hao
中科院分区：
文献类型：
--
作者：
Sun，Shan-Liang;Wu，Shi-Han;Shi，Zhi-Hao
尽管具有显著的功效，但小分子布鲁顿酪氨酸激酶（BTK）试剂的主要限制之一是存在临床获得性抗性，这仍然是一个主要的临床挑战。该观点侧重于开发针对耐药性的BTK小分子抑制剂的药物化学策略，包括针对点突变的BTK抑制剂的基于结构的设计，例如，(i)从共价抑制剂开发非共价抑制剂，（ii）避免突变残基的空间位阻，（iii）与突变残基相互作用，（iv）修饰溶剂可及区域，和（v）开发新的支架。此外，基于2916种独特的BTK配体和283种其他激酶之间的交叉比较，对BTK的多重抑制进行了比较分析，其中包括7108种双重/多重抑制。最后，针对BTK的变构位点和使用蛋白水解靶向嵌合体（PROTAC）作为两个潜在的战略简要介绍，同时也说明了可能性和挑战，以寻找新的BTK配体。
Despite significant efficacy, one of the major limitations of small-molecule Bruton’s tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g., (i) developing noncovalent inhibitors from covalent inhibitors, (ii) avoiding steric hindrance from mutated residues, (iii) making interactions with the mutated residue, (iv) modifying the solvent-accessible region, and (v) developing new scaffolds. Additionally, a comparative analysis of multi-inhibitions of BTK is presented based on cross-comparisons between 2916 unique BTK ligands and 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, targeting the BTK allosteric site and uding proteolysis-targeting chimera (PROTAC) as two potential strategies are addressed briefly, while also illustrating the possibilities and challenges to find novel ligands of BTK.