Design, synthesis and biological evaluation of structurally new 4-indolyl quinazoline derivatives as highly potent, selective and orally bioavailable EGFR inhibitors

Targeting the epidermal growth factor receptor (EGFR) has been recognized as an effective strategy for treating non-small-cell lung Cancer (NSCLC). Although several representative EGFR inhibitors have been approved for clinical use, it is highly desirable to develop highly potent and selective EGFR inhibitors with novel scaffolds because of the occurrence of acquired resistance after treatment. Here we first demonstrate that the 4-indolyl quinazoline derivatives could potently inhibit EGFR in vitro and in vivo, of which YS-67 effectively and selectively inhibits EGFR[WT] (IC50 = 5.2 nM), EGFR[d746-750] (IC50 = 9.6 nM) and EGFR[L858R] (IC50 = 1.9 nM). The TREEspot™ kinase interaction map further reveals the binding selectivity toward 468 kinases. YS-67 not only potently suppresses p-EGFR and p-AKT, but also effectively inhibits proliferation of A549 (IC₅₀ = 4.1 μM), PC-9 (IC₅₀ = 0.5 μM) and A431 cells (IC₅₀ = 2.1 μM). YS-67 treatment also causes colony formation inhibition, arrests cell cycle progression at G0/G1 phases and induces Apoptosis. More importantly, YS-67 is well tolerated in A431 xenograft model after oral administration, showing effective tumor growth suppression and low toxicity. Collectively, YS-67 represents an underexplored scaffold for developing new EGFR inhibitors.

4-Indolyl quinazoline; Biaryl scaffold; EGFR inhibitors; NSCLC.