RECENT ADVANCES IN PYRIMIDINE-BASED EGFR INHIBITORS: STRUCTURE–ACTIVITY RELATIONSHIPS, BIOLOGICAL EVALUATION AND MOLECULAR DOCKING

Abstract

Although conventional chemotherapy has proven to be the most effective treatment for the majority of cancers, even though the growing problems of chemotherapy's systemic toxicity and emergence of drug resistance have boosted the advancement of targeted therapeutic approaches to cancer. Based on the validated molecular targets, the EGFR is a notably attractive target to study. EGFR have its key functions in regulating the cell proliferation, survival, migration and tumor progression. The capacity of Pyrimidine based scaffolds to adopt essential interactions with the ATP binding domain of the receptor coupled with their beneficial structural features has made them privileged pharmacophores in the design of inhibitors against the EGFR. This review highlights the recent development of Pyrimidine based EGFR tyrosine kinase inhibitor with focus on structural diversity, synthesis, biological evaluation, molecular docking and structure–activity relationship (SAR) studies.The review presents representative compounds with nanomolar inhibitory activity against both wild-type and clinically relevant EGFR mutants (T790M and C797S) with the critical molecular interactions involving the hinge-region residues, hydrogen bonding, lipophilic interaction like  MET793, LYS745, CYS797 ,ASP855 and more.The review discuss about the approaches to overcome acquired resistance with mutant-selective and multi-target inhibitors. The review highlights importance of scaffold hybridization, linker optimization, electronic substituent effects and fused heterocyclic structures in the kinase selectivity and anticancer activity. Overall, these findings strengthen the current rationale for further optimization of Pyrimidine frameworks as a viable platform for the development of next generation anti-cancer drugs targeting the EGFR in order to achieve greater potency, selectivity and therapeutic potential.