作者: Linjiang Tong ; Xianglong Hu ; Mengzhen Lai ; Tao Huang ; Cai-Hong Yun ; Xiaoyun Lu ; Su-Jie Zhu ; Tao Zhang ; Qiuju Xun ; Ke Ding ; Qian Li ; Hua Xie

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 EGFR^C797S inhibitors.One of the most potent compound 6i potently suppressed EGFR^{L858R/T790M/C797S} kinase with an IC₅₀ value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} mutants with IC₅₀ values of 290 nmol/L and 316 nmol/L, resp.Further, 6i dose-dependently induced suppression of the phosphorylation of EGFR^{L858R/T790M/C797S} and EGFR^{19D/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.

2019-08-08·Journal of medicinal chemistry1区 · 医学

Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR^{L858R/T790M/C797S})

1区 · 医学

Article

作者: Sun, Min ; Zhu, Su-Jie ; Lu, Xiaoyun ; Shen, Jiayi ; Xie, Hua ; Xu, Wei ; Ding, Jian ; Zhang, Rong ; Lai, Mengzhen ; Ding, Ke ; Zhang, Tao ; Tong, Linjiang ; Wu, Ruibo ; Yun, Cai-Hong

Tertiary EGFR^C797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR^{L858R/T790M/C797S} inhibitors. A representative compound, 8r-B, exhibited an IC₅₀ of 27.5 nM against the EGFR^{L858R/T790M/C797S} mutant, while being a significantly less potent for EGFR^WT (IC₅₀ > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

2018-11-08·ACS medicinal chemistry letters3区 · 医学

Discovery of JND3229 as a New EGFR^C797S Mutant Inhibitor with In Vivo Monodrug Efficacy

3区 · 医学

Article

作者: Ding, Ke ; Zhu, Su-Jie ; Tong, Lingjiang ; Hu, Xianglong ; Chan, Shingpan ; Li, Yan ; Xie, Hua ; Sun, Yiming ; Ding, Jian ; Xun, Qiuju ; Su, Yi ; Lu, Xiaoyun ; Yun, Cai-Hong ; Zhang, Tao ; Chen, Yi

EGFR^C797S 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 EGFR^C797S 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/EGFR^{19D/T790M/C797S} cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFR^T790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFR^C797S inhibitors as anticancer drugs.

100 项与 JND-3229 相关的药物交易

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