Design, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRASG12C inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer

  • Eur J Med Chem. 2022 Dec 15;244:114808. doi: 10.1016/j.ejmech.2022.114808.
Rongjie Cheng  1 ,  Xiashi Lv  2 ,  Huagang Bu  1 ,  Qiaoliang Xu  2 ,  Jianzhuang Wu  1 ,  Kexin Xie  1 ,  Jiaqi Tang  2 ,  Lei Wang  2 ,  Jian Zhuang  2 ,  Yihua Zhang  2 ,  Yaliang Zhang  3 ,  Chao Yan  4 ,  Yisheng Lai  5
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 2. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
  • 3. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 36228411 DOI: 10.1016/j.ejmech.2022.114808
Abstract

KRASG12C is the most prevalent KRAS mutation in non-small cell lung Cancer (NSCLC) and has emerged as a promising therapeutic target. Herein, two series of novel 4(1H)-quinolinone and urea compounds were designed based on the reported KRASG12C inhibitor SH-9. Many compounds showed significantly growth inhibitory activity against human NSCLC cells with KRASG12C mutation in cell viability assays. Compound 20a exhibited an IC50 value of 0.5 μM in KRASG12C-mutant NCI-H358 cells with 21-fold selectivity over KRASWT NCI-H2228 cells. LC-MS analysis indicated that compounds 14c, 14h and 20a covalently bound to KRASG12C rather than KRASWT. Moreover, these compounds could remarkably trap KRASG12C in its inactive state by blocking SOS1-mediated GDP/GTP exchange. Furthermore, treatment of NCI-H358 but not NCI-H2228 cells with 20a dose-dependently reduced the phosphorylation of KRAS downstream effectors ERK and Akt. Importantly, 20a significantly inhibited tumor growth in NCI-H358 xenograft models by suppressing KRASG12C signalling. These results indicate that 20a is a promising candidate worthy of further investigation.

Keywords
4(1H)-quinolinone; Covalent inhibitor; KRAS(G12C) mutation; Non-small cell lung cancer; Urea.
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