Discovery of EGF Receptor Inhibitors That Are Selective for the d746‐750/T790M/C797S Mutant through Structure‐Based de Novo Design

Abstract

Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.

Automated De Novo Drug Design: Are We Nearly There Yet?

“…having an IC 50 value of 0.012 nm.T he same group has reported similar approaches against other kinase targets, including mutant EGFR, [33] GSK3b, [34] p38, [35] and Abl kinase, [36] showing the generality of the approach, at least within this target family.H ere again, novel and potent compounds have resulted from the exercise but de novo design is only part of the overall process.…”

Automated De Novo Drug Design: Are We Nearly There Yet?

“…Out of this group, picomolar inhibitors were identified, the best of these ( 6 ; Figure ) having an IC 50 value of 0.012 n m . The same group has reported similar approaches against other kinase targets, including mutant EGFR, GSK3β, p38, and Abl kinase, showing the generality of the approach, at least within this target family. Here again, novel and potent compounds have resulted from the exercise but de novo design is only part of the overall process.…”

Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry

“…Recently, the 2‐aryl‐4‐aminoquinazoline‐based hit 29 was reported as a fourth‐generation EGFR del746‐750/T790M/C797S triple mutant inhibitor derived from virtual screening and de novo design . The enzymatic assays showed that compound 29 has potent EGFR del746‐750/T790M/C797S kinase inhibitory activity with an IC 50 value of 149 nM.…”