Medicinal Chemistry Strategies for the Development of Bruton’s Tyrosine Kinase Inhibitors against Resistance,Journal of Medicinal Chemistry

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Medicinal Chemistry Strategies for the Development of Bruton’s Tyrosine Kinase Inhibitors against Resistance
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-20 , DOI: 10.1021/acs.jmedchem.2c00030
Shan-Liang Sun ₁ , Shi-Han Wu ₁ , Ji-Bo Kang ₁ , Yi-Yuan Ma ₁ , Lu Chen ₁ , Peng Cao _{1,

2} , Liang Chang ₁ , Ning Ding ₁ , Xin Xue ₁ , Nian-Guang Li ₁ , Zhi-Hao Shi ₃

Affiliation

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.

中文翻译：

开发抗布鲁顿酪氨酸激酶抑制剂的药物化学策略

尽管疗效显着，但小分子布鲁顿酪氨酸激酶 (BTK) 药物的主要限制之一是存在临床获得性耐药性，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，包括基于结构的 BTK 抑制剂靶向点突变设计，例如，（i）从共价抑制剂开发非共价抑制剂，（ii）避免空间位阻从突变的残基，（iii）与突变的残基相互作用，（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 种涵盖 7108 种双重/多重抑制的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。最后，简要介绍了靶向 BTK 变构位点和使用蛋白水解靶向嵌合体 (PROTAC) 作为两种潜在策略，同时也说明了寻找 BTK 新配体的可能性和挑战。

更新日期：2022-05-20

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