A novel multi-target inhibitor harboring selectivity of inhibiting EGFR T790M sparing wild-type EGFR.

Non-Small Cell Lung Cancer (NSCLC) is driven by a variety of deregulated kinases and the development of multi-target inhibitor for multiple signaling pathways or multiple steps is required. Here, we reported that ZWM026, an indolocarbazoles analogue, derived from mangrove in coastal marine wetland, exhibited selectivity and reversibility against T790M mutant over wild-type EGFR in naturally occurring NSCLC cells and constructed NIH-3T3 cells. It simultaneously inhibited activities of HER2, HER3, HER4 and RET but was different from current multi-target kinase inhibitors. There was no activity in protein kinase C (PKC) family which is generally recognized as molecule target of indolocarbazoles. ZWM026 had more potent activities against gefitinib sensitizing, non-sensitizing and rare EGFR mutant NSCLC cells and constructed NIH-3T3 cells. ZWM026 induced apoptosis and exerted a synergistic effect by combining with cisplatin in NCI-H1975 cells. In summary, we identified a novel reversible multi-target inhibitor which could serve as a promising lead compound of drug development for NSCLC.