#165 Design and synthesis of allosteric fourth-generation EGFR tyrosine kinase triple mutant selective inhibitors for the treatment of non-small cell lung cancer

How to Cite

Zakir, A. A. .; Mohd Siddique, M. U. #165 Design and Synthesis of Allosteric Fourth-Generation EGFR Tyrosine Kinase Triple Mutant Selective Inhibitors for the Treatment of Non-Small Cell Lung Cancer. J Pharm Chem 2022, 8.


Non-small cell lung cancer (NSCLC) is the leading cause of mortality in oncology, and EGFR-TK plays a critical role in this disease. As a result, EGFR-TK is a viable target for therapeutic development in NSCLC. The T790M EGFR TK mutation was resistant to both first-generation and second-generation (selectivity issue) EGFR TK inhibitors. Although third-generation drugs (Osimertinib) can overcome the EGFR T790M mutation, a recent C797S mutation makes these agents ineffective against it. All of the currently available EGFR kinase inhibitors target the kinase’s highly conserved ATP-site, underlining the need for therapeutics with a different mechanism of action (allosteric binding). EAI001, EAI045, JBJ-04-125-02, DDC4002, and a series of small compounds (fourth generation) having an affinity for the EGFR allosteric site have been discovered and are currently being investigated. To overcome EGFR T790M/C797S resistance, allosteric mutant-selective fourth-generation EGFR inhibitors look to be a promising treatment approach. We present the discovery, development, and structural characterization of allosteric mutant selective EGFR inhibitors based on an anilino pyrimidine scaffold. Our structure-based medicinal chemistry effort resulted in an inhibitor (3) of the EGFR (L858R/T790M) and EGFR (L858R/T790M/C797S) mutants with an IC50 of 10 nM and good selectivity, as shown by kinome profiling. Further research into allosteric anilinopyrimidine inhibitors might pave the way for new treatment alternatives for targeting drug-resistant EGFR mutations.



Creative Commons License

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Copyright (c) 2022 Journal of Pharmaceutical Chemistry