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

Xuanzheng Xiao; Mengzhen Lai; Zilan Song; Meiyu Geng; Jian Ding; Hua Xie; Ao Zhang

doi:10.1016/j.ejmech.2020.113082

Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS^G12C inhibitors

Eur J Med Chem. 2021 Mar 5:213:113082. doi: 10.1016/j.ejmech.2020.113082. Epub 2020 Dec 4.

Authors

Xuanzheng Xiao¹, Mengzhen Lai², Zilan Song¹, Meiyu Geng³, Jian Ding³, Hua Xie⁴, Ao Zhang⁵

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 (KRAS^G12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS^G12C 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 KRAS^G12C 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.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclization
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Molecular Docking Simulation
Oncogenes / drug effects
Pancreatic Neoplasms / drug therapy*
Phosphorylation / drug effects
Piperazines / chemical synthesis*
Piperazines / pharmacology
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
Proto-Oncogene Proteins p21(ras) / genetics
Pyridines / chemical synthesis*
Pyridines / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology
Signal Transduction
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Piperazines
Pyridines
Pyrimidines
sotorasib
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases
Proto-Oncogene Proteins p21(ras)