Design and Modeling of 4-Anilinoquinazoline Derivatives as Small Molecule Inhibitors of T790M/C797S EGFR Mutations to Abandon the Phenomenon of Tumor Angiogenesis

In most types of cancers, specifically, lung cancer, glioblastoma, and breast cancer, the EGFR tyrosine kinase mostly remains in an overactivation state due to the developed mutations in a few specific residues of the kinase domain of protein EGFR.

The overexpression of EGFR results in the activation of signaling pathways responsible for the proliferation, growth, metastasis, and neo-angiogenesis in different types of cancers. The different mutations found in cancers expressing the EGFR include L858R, T790, and C797S and other uncommon mutations like S786R, C761X, and L861Q mutations. In the treatment with first-generation EGFR tyrosine kinase inhibitors like erlotinib and gefitinib, cancers have developed secondary resistance due to the development of secondary mutations like T790M.

It was first proposed that T790M mutations do not block the binding of the inhibitors, but later on, it was found that T790M mutations restore the ATP binding affinity of the kinase domain of EGFR monomers. Therefore, the first-generation inhibitors are not able to bind to T790M mutated EGFR. The second-generation 4-anilino quinazoline-based EGFR inhibitors like dacomitinib and afatinib have shown excellent binding potency with EGFR (T790M) but suffer serious side effects, which urges us to search for new small molecules, which may have the potential to inhibit the tumor angiogenic signals associated with over-activated EGFR.

In this study, new 4-anilino quinazoline inhibitors as small molecule inhibitors were discovered to target T790M/C797S mutations in EGFR using structure-based virtual screening, docking, and metabolic reactivity studies against the phenomenon of tumor angiogenesis.