Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2

Shaofeng Sun; Zuopeng He; Mindong Huang; Ningning Wang; Zongzhong He; Xiangkai Kong; Jianwen Yao

doi:10.1016/j.bmc.2018.03.039

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-Raf^V600E and VEGFR-2

Bioorg Med Chem. 2018 May 15;26(9):2381-2391. doi: 10.1016/j.bmc.2018.03.039. Epub 2018 Apr 3.

Authors

Shaofeng Sun¹, Zuopeng He¹, Mindong Huang¹, Ningning Wang¹, Zongzhong He², Xiangkai Kong¹, Jianwen Yao³

Affiliations

¹ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, 30 Qingquan Road, Yantai, Shandong 264005, PR China.
² Molecular Biology Division, Yantai Aillen Biological Technology Co., Ltd., 9 Keji Road, Yantai, Shandong 264670, PR China.
³ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, 30 Qingquan Road, Yantai, Shandong 264005, PR China. Electronic address: jwy5610201@163.com.

PMID: 29631788
DOI: 10.1016/j.bmc.2018.03.039

Abstract

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf^V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf^V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC₅₀ of 21 nM, 27 nM and 17 nM, B-Raf^V600E with IC₅₀ of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC₅₀ of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.

Keywords: Antitumor; B-Raf; Kinase inhibitor; Nicotinamide; VEGFR-2.

Publication types

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

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
Enzyme Assays
Humans
Hydrogen Bonding
Mice
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / chemistry
Proto-Oncogene Proteins B-raf / genetics
Sorafenib / chemical synthesis
Sorafenib / pharmacology*
Sulfides / chemical synthesis
Sulfides / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
Sulfides
Sorafenib
Vascular Endothelial Growth Factor Receptor-2
Proto-Oncogene Proteins B-raf