Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

• DOI: 10.1073/pnas.1403438111
• Publication Date: 2014-10-28T07:24:15Z
• Authors: Li Tan; Jun Wang; Junko Tanizaki; Zhifeng Huang; Amir R. Aref; Maria Rusan; Su-Jie Zhu; Yiyun Zhang; Dalia Ercan; Rachel G. Liao; Marzia Capelletti; Wenjun Zhou; Wooyoung Hur; NamDoo Kim; Taebo Sim; Suzanne Gaudet; David A. Barbie; Jing-Ruey Joanna Yeh; Cai-Hong Yun; Peter S. Hammerman; Moosa Mohammadi; Pasi A. Jänne; Nathanael S. Gray
• Keywords: 0301 basic medicine; Binding Sites; Mutation, Missense; Antineoplastic Agents; Crystallography, X-Ray; 3. Good health; ErbB Receptors; Structure-Activity Relationship; 03 medical and health sciences; Amino Acid Substitution; Drug Resistance, Neoplasm; Cell Line, Tumor; Neoplasms; Humans; Receptor, Fibroblast Growth Factor, Type 4; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Protein Kinase Inhibitors

Significance Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for treatment various cancers. All approved kinase inhibitors eventually rendered useless by emergence drug-resistant tumors. We used structure-based drug design to develop first, our knowledge, selective, next-generation covalent FGFR that can overcome most common form inhibitor resistance, mutation so-called “gatekeeper” residue located in ATP-binding pocket. also describe a novel strategy uses single electrophile target covalently cysteines different positions within These results have important implications resistance.