SARs of a novel series of s-triazine compounds targeting vimentin to induce methuotic phenotype

Lei Zhang; Zhipeng Qu; Jianping Wu; Shining Yao; Qingqing Zhang; Tao Zhang; Lian Mo; Qizheng Yao; Ying Xu; Ruihuan Chen

doi:10.1016/j.ejmech.2021.113188

SARs of a novel series of s-triazine compounds targeting vimentin to induce methuotic phenotype

Eur J Med Chem. 2021 Mar 15:214:113188. doi: 10.1016/j.ejmech.2021.113188. Epub 2021 Jan 18.

Authors

Lei Zhang¹, Zhipeng Qu², Jianping Wu³, Shining Yao⁴, Qingqing Zhang⁵, Tao Zhang⁶, Lian Mo⁷, Qizheng Yao⁸, Ying Xu⁹, Ruihuan Chen¹⁰

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China. Electronic address: [email protected].
² Cambridge-Suda Genomic Resource Center, Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Luoda Biosciences, Inc., Chuzhou, Auhui, 239234, China.
³ Luoda Biosciences, Inc., Chuzhou, Auhui, 239234, China; Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210046, China.
⁴ Najing Shiqi Pharmaceutical Co. Ltd., Nanjing, Jiangsu, 211198, China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
⁶ Cambridge-Suda Genomic Resource Center, Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
⁷ Aluda Pharmaceuticals, Inc., Union City, CA, 94587, USA.
⁸ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China. Electronic address: [email protected].
⁹ Cambridge-Suda Genomic Resource Center, Medical College of Soochow University, Suzhou, Jiangsu, 215123, China. Electronic address: [email protected].
¹⁰ Cambridge-Suda Genomic Resource Center, Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Luoda Biosciences, Inc., Chuzhou, Auhui, 239234, China; Aluda Pharmaceuticals, Inc., Union City, CA, 94587, USA. Electronic address: [email protected].

PMID: 33550185
DOI: 10.1016/j.ejmech.2021.113188

Abstract

Herein, we describe the design, synthesis and structure-activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6, exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure-activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at ²⁷³R and ²⁷⁶Y in its rod domain.

Keywords: Cancer; Methuosis; Target; Vimentin; s-Triazine derivatives.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Phenotype
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*
Tumor Cells, Cultured
Vimentin / antagonists & inhibitors*
Vimentin / genetics
Vimentin / metabolism

Substances

Antineoplastic Agents
Triazines
VIM protein, human
Vimentin