2260886-64-2Relevant academic research and scientific papers
Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with in Vivo Monodrug Efficacy
Lu, Xiaoyun,Zhang, Tao,Zhu, Su-Jie,Xun, Qiuju,Tong, Lingjiang,Hu, Xianglong,Li, Yan,Chan, Shingpan,Su, Yi,Sun, Yiming,Chen, Yi,Ding, Jian,Yun, Cai-Hong,Xie, Hua,Ding, Ke
, p. 1123 - 1127 (2018)
EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging unmet clinical need for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.
2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant
Hu, Xianglong,Xun, Qiuju,Zhang, Tao,Zhu, Su-Jie,Li, Qian,Tong, Linjiang,Lai, Mengzhen,Huang, Tao,Yun, Cai-Hong,Xie, Hua,Ding, Ke,Lu, Xiaoyun
, p. 1281 - 1287 (2019/10/14)
Extensive 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.
