2. Academic Validation
  3. The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations

The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations

  • Eur J Med Chem. 2021 Nov 15:224:113711. doi: 10.1016/j.ejmech.2021.113711.
Zhenqiang Xia 1,  Ridong Huang 1,  Xinglong Zhou 1,  Yingying Chai 1,  Hai Chen 1,  Lingling Ma 1,  Quanwei Yu 1,  Ying Li 1,  Weimin Li 2,  Yang He 3
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China; Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China; Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China.
  • 2 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China; Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China; Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China. Electronic address: weimi003@scu.edu.cn.
  • 3 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, PR China; Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China; Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, PR China. Electronic address: heyangqx@scu.edu.cn.
PMID: 34315040 DOI: 10.1016/j.ejmech.2021.113711
Abstract

EGFR mutations are an ongoing challenge in the treatment of NSCLC, and demand continuous updating of EGFR TKI drug candidates. Pyrrolopyrimidines are one group of versatile scaffolds suitable for tailored drug development. However not many precedents of this type of pharmacophore have been investigated in the realm of third generation of covalent EGFR-TKIs. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives able to block mutant EGFR activity in a covalent manner were synthesized, through optimized Buchwald-Hartwig C-N cross coupling reactions. Their preliminary bioactivity and corresponding inhibitory mechanistic pathways were investigated at molecular and cellular levels. Several compounds exhibited increased biological activity and enhanced selectivity compared to the control compound. Notably, compound 12i selectively inhibits HCC827 cells harboring the EGFR activating mutation with up to 493-fold increased efficacy compared to in normal HBE cells. Augmented selectivity was also confirmed by kinase enzymatic assay, with the test compound selectively inhibiting the T790 M activating mutant EGFRs (IC50 values of 0.21 nM) with up to 104-fold potency compared to the wild-type EGFR (IC50 values of 22 nM). Theoretical simulations provide structural evidence of selective kinase inhibitory activity. Thus, this series of pyrrolo[2,3-d]pyrimidine derivatives could serve as a starting point for the development of new EGFR-TKIs.

Keywords

EGFR; NSCLC; Pyrrolo[2,3-d]pyrimidine; TKIs.

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