Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAFV600E inhibition

Hong-Lin Li; Mi-Mi Su; Yun-Jie Xu; Chen Xu; Yu-Shun Yang; Hai-Liang Zhu

doi:10.1016/j.ejmech.2018.06.043

Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAF^V600E inhibition

Eur J Med Chem. 2018 Jul 15:155:725-735. doi: 10.1016/j.ejmech.2018.06.043. Epub 2018 Jun 19.

Authors

Hong-Lin Li¹, Mi-Mi Su¹, Yun-Jie Xu¹, Chen Xu², Yu-Shun Yang³, Hai-Liang Zhu⁴

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China. Electronic address: xuchn@nju.edu.cn.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China; Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China. Electronic address: ys_yang@nju.edu.cn.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China; Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China. Electronic address: zhuhl@nju.edu.cn.

PMID: 29940463
DOI: 10.1016/j.ejmech.2018.06.043

Abstract

A series of novel selective BRAF^V600E inhibitory agents (Compound 1-16) 5-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-N,3-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamides have been designed and synthesized. Their anti-proliferation and BRAF inhibitory activities were evaluated. Though 15, 4 and 12 all displayed comparable activity with the positive control Vemurafenib, only 12 indicated fine selectivity on BRAF^V600E (IC50 = 0.06 μM for BRAF^V600E; GI50 = 0.52 μM for A375) over BRAF^WT at both kinase and cell levels. This result satisfied the designing concept of improving activity and introducing selectivity. Flow cytometry analysis and western blot convinced the apoptosis induction and kinase inhibitory activity. Docking simulation inferred the differences in binding patterns of BRAF^V600E and BRAF^WT, pointing out that the future orientation might be seeking for outer space binding of BRAF^V600E and avoiding interactions with HIS573 of BRAF^WT. These results brought potent BRAF inhibitors one step further to selective agents, enhancing the potential for safe medication.

Keywords: Antitumor; Apoptosis induction; BRAF(V600E); Dioxane; Selectivity; Triaryl pyrazoline.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line
Cell Proliferation / drug effects
Dioxanes / chemistry
Dioxanes / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Dioxanes
Protein Kinase Inhibitors
Pyrazoles
pyrazole
Proto-Oncogene Proteins B-raf