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Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor |
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| Authors: | Qi-Zheng Sun Yong Xu Jing-Jing Liu Chun-Hui Zhang Ze-Rong Wang Ren-Lin Zheng Wen-Jing Wang Lin-Li Li Sheng-Yong Yang |
| Affiliation: | 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China 2. West China School of pharmacy, Sichuan University, No. 17, Renmin Road South, Chengdu, Sichuan, China 3. School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China |
| Abstract: | Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an $hbox {IC}_{50}$ value of 7 nM. |
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