Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR

Abstract

EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR. Herein, we report the design, synthesis and in vitro testing of a series of analogues of the previously identified hit with the aim of exploring the structure-activity relationships (SAR) around this scaffold. The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation.

GRAPHICAL ABSTRACT

Keywords:

• EGFR inhibitors
• allosteric inhibitors
• anticancer drugs
• drug design

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro [AIRC IG 15993 to G.R. and AIRC IG 24828 to L.M]. Financial support from Legacoop Estense to GR is also gratefully acknowledged.