2-Oxo-3,4-dihydropyrimido[4, 5-d] Pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant

Publication date: Available online 24 September 2019Source: Chinese Chemical LettersAuthor(s): Xianglong Hu, Qiuju Xun, Tao Zhang, Su-Jie Zhu, Qian Li, Linjiang Tong, Mengzhen Lai, Tao Huang, Cai-Hong Yun, Hua Xie, Ke Ding, Xiaoyun LuAbstractExtensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFRC797S inhibitors. One of the most potent compound 6i potently suppressed EGFRL858R/T790M/C797S kinase with an IC50 value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutants with IC50 values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.Graphical AbstractA new series of 2-oxo-3,4-dihydropyrimido[4, 5-d] pyrimidines was designed and synthesized as new reversible inhibitors of EGFRC797S mutant to overcome drug resistant NSCLC. One of the most potent compound 6i potently suppressed EGFRL858R/T790M/C797S kinase with an IC50 value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutants with IC50 values of 290 nmol/L and 316...
Source: Chinese Chemical Letters - Category: Chemistry Source Type: research