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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Aberrant activity of epidermal growth factor receptor (EGFR) is implicated in drug-resistant non-small cell lung cancer (NSCLC).
• Allosteric inhibition of EGFR presents a promising strategy for developing novel anticancer drugs.
• A previous study identified a type III allosteric inhibitor for the L858R/T790M double mutant EGFR.

Purpose of the Study:

• To design, synthesize, and evaluate analogues of a previously identified hit compound.
• To explore structure-activity relationships (SAR) for type III allosteric inhibition of double mutant EGFR.
• To identify novel compounds with improved inhibition and antiproliferative activity against NSCLC cells.

Main Methods:

• Chemical synthesis of EGFR inhibitor analogues.
• In vitro testing to assess enzyme inhibition.
• Antiproliferative assays using H1975 NSCLC cell line.

Main Results:

• Identified two compounds, designated 15 and 18, with enhanced inhibition of double mutant EGFR compared to the original hit.
• Compounds 15 and 18 demonstrated significant antiproliferative activity against H1975 NSCLC cells.
• Structure-activity relationship exploration guided the optimisation of the inhibitor scaffold.

Conclusions:

• Compounds 15 and 18 are promising starting points for further hit-to-lead optimization in NSCLC drug development.
• The identified analogues represent potential therapeutic agents against EGFR-driven resistant lung cancers.
• Further research is warranted to develop these compounds into clinically viable drugs.