期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 19, 页码 10726-10741出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00507
关键词
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资金
- National Natural Science Foundation of China [81922062, 81874285]
- National Key Research and Development Program of China [2018YFE0105800]
- Guangdong Provincial Science and Technology program [2018A050506043]
- Jinan University, Health Research Council of New Zealand [18/1016]
- Cancer Society Auckland Northland
Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major unmet clinical need in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.
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