title: Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor.
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 IC(50) value of 7 nM.
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China.
authors: Qi-Zheng
authors: QZ
authors: Sun
authors: Yong
authors: Y
authors: Xu
authors: Jing-Jing
authors: JJ
authors: Liu
authors: Chun-Hui
authors: CH
authors: Zhang
authors: Ze-Rong
authors: ZR
authors: Wang
authors: Ren-Lin
authors: RL
authors: Zheng
authors: Wen-Jing
authors: WJ
authors: Wang
authors: Lin-Li
authors: LL
authors: Li
authors: Sheng-Yong
authors: SY
authors: Yang
mesh_terms: D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret