2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRASG12C inhibitors

Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRASG12C inhibitors

  • Eur J Med Chem. 2021 Mar 5:213:113082. doi: 10.1016/j.ejmech.2020.113082.
Xuanzheng Xiao 1,  Mengzhen Lai 2,  Zilan Song 1,  Meiyu Geng 3,  Jian Ding 3,  Hua Xie 4,  Ao Zhang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: hxie@simm.ac.cn.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: ao6919zhang@sjtu.edu.cn.
PMID: 33309163 DOI: 10.1016/j.ejmech.2020.113082
Abstract

KRAS is the most commonly altered oncogene of the Ras family, especially the G12C mutant (KRASG12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRASG12C inhibitor AMG510, a scaffold hopping strategy was conducted including a F-OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 μM against KRASG12C and cell growth inhibition of 0.79 μM in MIA PaCa-2 pancreatic Cancer cells. Treatment of 26a with NCI-H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and Akt dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification.

Keywords

Antiproliferative effect; Covalent inhibitor; KRAS; Pyridopyrimidinone; Scaffold hopping.

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