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The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations
- Source :
- European journal of medicinal chemistry. 224
- Publication Year :
- 2021
-
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.
- Subjects :
- Lung Neoplasms
Pyrimidine
Mutant
Antineoplastic Agents
Cell Line
chemistry.chemical_compound
Structure-Activity Relationship
Carcinoma, Non-Small-Cell Lung
Drug Discovery
Humans
Pyrroles
Protein Kinase Inhibitors
Cell Proliferation
Pharmacology
chemistry.chemical_classification
Dose-Response Relationship, Drug
Molecular Structure
Kinase
Organic Chemistry
Cell Cycle
Biological activity
General Medicine
ErbB Receptors
Molecular Docking Simulation
Enzyme
Pyrimidines
chemistry
Biochemistry
Mutation
EGFR Activating Mutation
Pharmacophore
Drug Screening Assays, Antitumor
Tyrosine kinase
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 224
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....15e843e6b2fef4a1f74954363286451c