A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties

Lei Yu; Minhao Huang; Tianfeng Xu; Linjiang Tong; Xiao-E Yan; Zhang Zhang; Yong Xu; Caihong Yun; Hua Xie; Ke Ding; Xiaoyun Lu

doi:10.1016/j.ejmech.2016.12.006

A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR^L858R/T790M mutant with improved pharmacokinetic properties

Eur J Med Chem. 2017 Jan 27:126:1107-1117. doi: 10.1016/j.ejmech.2016.12.006. Epub 2016 Dec 3.

Authors

Lei Yu¹, Minhao Huang¹, Tianfeng Xu¹, Linjiang Tong², Xiao-E Yan³, Zhang Zhang⁴, Yong Xu⁴, Caihong Yun³, Hua Xie⁵, Ke Ding⁶, Xiaoyun Lu⁷

Affiliations

¹ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
³ Peking University Institute of Systems Biomedicine and Department of Biophysics, Peking University Health Science Center, Beijing 100191, China.
⁴ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
⁶ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: ding_ke@gibh.ac.cn.
⁷ School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: luxy2016@jnu.edu.cn.

PMID: 28033579
DOI: 10.1016/j.ejmech.2016.12.006

Abstract

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR^T790M inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR^L858R/T790M kinase and inhibited the proliferation of H1975 cells with IC₅₀ values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

Keywords: EGFR(T790M) mutant; Irreversible inhibitor; NSCLC; Pharmacokinetic property; Pyrido[2,3-d]pyrimidin-7-ones.

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Biological Availability
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Drug Resistance, Neoplasm / drug effects
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / chemistry
ErbB Receptors / genetics*
Humans
Male
Models, Molecular
Mutation*
Protein Conformation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacokinetics*
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
ErbB Receptors