期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 11, 页码 7415-7437出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00030
关键词
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资金
- National Natural Science Foundation of China [81973171, 81502986, 82103985, 82103987]
- National Natural Science Fund for Outstanding Youth Fund [81622048]
- Natural Science Foundation of Jiangsu Provincial Colleges and Universities [21KJB350005, 21KJB350006]
- Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine [2020YLXK002]
- Natural Science Foundation of Jiangsu Province [BK20151563]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX201561]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Flagship Major Development of Jiangsu Higher Education Institutions [PPZY2015A070]
- Key Laboratory of Therapeutic Material of Chinese Medicine, Jiangsu Province, State Key Laboratory Cultivation Base for TCM Quality and Efficacy
- Nanjing University of Chinese Medicine
This Perspective article focuses on medicinal chemistry strategies for developing small-molecule BTK inhibitors against resistance. It discusses the structure-based design of BTK inhibitors targeting point mutations and other strategies to overcome resistance, as well as comparative analysis of multi-inhibitions of BTK. The article also briefly addresses allosteric targeting of BTK and the use of PROTAC as potential strategies for finding novel BTK ligands.
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 crosscomparisons 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.
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