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

Longcai Cao; Han Yao; Linlin Yu; Yuanyuan Ren; Jiadai Liu; Xingshu Li; Xian Jia

doi:10.1016/j.bmc.2023.117241

Synthesis and evaluation of sulfonamide derivatives targeting EGFR^790M/L858R mutations and ALK rearrangement as anticancer agents

Bioorg Med Chem. 2023 May 1:85:117241. doi: 10.1016/j.bmc.2023.117241. Epub 2023 Mar 17.

Authors

Longcai Cao¹, Han Yao², Linlin Yu¹, Yuanyuan Ren², Jiadai Liu¹, Xingshu Li³, Xian Jia⁴

Affiliations

¹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Guangdong Provincial Key Laboratory of Drug Non-clinical Evaluation and Research, China.
³ Guangdong Provincial Key Laboratory of Drug Non-clinical Evaluation and Research, China. Electronic address: lixsh@mail.sysu.edu.cn.
⁴ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: jiaxian@syphu.edu.cn.

PMID: 37087886
DOI: 10.1016/j.bmc.2023.117241

Abstract

Fourteen new compounds bearing sulfonamide groups that target EGFRT^790M/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 (EGFR^T790M/L858R high express) and H2228 cells (ALK rearrangement) with the IC₅₀ values of 0.0215 μM and 0.011 μM, 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.

Keywords: ALK rearrangement; Anticancer; Cyclopropyl; EGFR mutations; Sulfonamide derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors
Humans
Lung Neoplasms* / drug therapy
Mutation
Protein Kinase Inhibitors
Structure-Activity Relationship

Substances

ErbB Receptors
Protein Kinase Inhibitors
Antineoplastic Agents
EGFR protein, human