Structure based designing of triazolopyrimidone-based reversible inhibitors for kinases involved in NSCLC

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) often develops resistance to therapies targeting mutant epidermal growth factor receptor (EGFR), specifically the L858R-T790M mutation.
• Amplification of the cMET receptor tyrosine kinase is another mechanism contributing to resistance in EGFR-mutant NSCLC.
• Targeting both EGFR (L858R-T790M) and cMET is crucial for overcoming acquired resistance in NSCLC.

Purpose of the Study:

• To design and synthesize novel small molecule dual inhibitors targeting EGFR (L858R-T790M) and cMET.
• To evaluate the in vitro biochemical and anti-proliferative activity of these novel inhibitors against resistant NSCLC models.

Main Methods:

• Utilized a triazolo-pyrimidone scaffold from previous lead molecules for developing dual inhibitors.
• Employed molecular sketching, docking, and molecular dynamics simulations to identify promising analogues.
• Synthesized selected analogues and performed in vitro biochemical assays against EGFR (L858R-T790M), cMET, and EGFR (L858R) kinases.
• Conducted in vitro anti-proliferative assays using NSCLC cell lines (A549, A431, H460).

Main Results:

• Identified three compounds with significant dual kinase inhibitory potential against EGFR (L858R-T790M) and cMET, with IC50 values below 100 nM.
• Two synthesized compounds demonstrated significant potency in in vitro anti-proliferative assays against tested NSCLC cell lines.

Conclusions:

• The developed small molecules represent promising dual inhibitors for overcoming resistance in NSCLC.
• These compounds effectively inhibit both EGFR (L858R-T790M) and cMET kinases, offering a potential therapeutic strategy for resistant NSCLC.