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

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.

尽管小分子布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase, BTK）抑制剂已展现出显著的临床疗效，但其主要局限性之一在于临床获得性耐药的产生，这仍是当前亟待解决的重大临床难题。本评述聚焦于针对耐药性开发BTK小分子抑制剂的药物化学策略，包括靶向点突变的BTK抑制剂的基于结构设计方法，例如：(1) 从共价抑制剂开发非共价抑制剂；(2) 规避突变残基带来的空间位阻；(3) 与突变残基形成相互作用；(4) 修饰溶剂可及区域；(5) 开发全新母核结构。此外，本研究基于2916种独特BTK配体与283种其他激酶的交叉比对，开展了BTK多靶点抑制特性的比较分析，共涵盖7108项双重/多重抑制数据。最后，本文简要探讨了以BTK变构位点为靶点以及采用蛋白降解靶向嵌合体（proteolysis-targeting chimera, PROTAC）这两种潜在策略，并同时阐明了开发新型BTK配体所面临的机遇与挑战。