Synthesis and evaluation of sulfonamide derivatives targeting EGFR790M/L858R mutations and ALK rearrangement as anticancer agents

Fourteen new compounds bearing sulfonamide groups that target EGFRT790M/L858R mutations and ALK rearrangement were synthesized and evaluated as dual-target tumor inhibitors. The study on the anti-proliferation activity on cancer cells showed that the sulfonamide derivative with pyrimidine nucleus had much better activities compared with those with quinazoline nucleus. Among them, compound 19e exhibited excellent activity against H1975 cancer cell lines (EGFRT790M/L858R high express) and H2228 cells (ALK rearrangement) with the IC50 values of 0.0215 mu M and 0.011 mu M, respectively. The ALK and EGFR kinase inhibition assays also provided similar results. Genotype selectivity of EGFR on kinase and cell level, cytotoxicity towards human normal cell lines and cell morphology assay implied that 19e had acceptable selectivity and low toxicity. In addition, the inhibitory activity of 19e on H1975 and H2228 cells cloning and its apoptosis-inducing effect on the two cell lines were studied, and its inhibitory effect on the invasion and migration of tumor cells were also investigated. All the results show that 19e is worthy of further study.

Automated summary

This study synthesized 14 new compounds with sulfonamide groups that target EGFRT790M/L858R mutations and ALK rearrangement, and evaluated them as dual-target tumor inhibitors. The sulfonamide derivative with a pyrimidine nucleus showed better activity than those with a quinazoline nucleus in anti-proliferation activity on cancer cells. Compound 19e exhibited excellent activity against H1975 cancer cell lines (EGFRT790M/L858R high express) and H2228 cells (ALK rearrangement) with low IC50 values. Further studies on 19e's inhibitory effects on cloning, apoptosis-inducing, invasion, and migration of tumor cells confirmed its potential and worth for further research.