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

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

  • Bioorg Med Chem. 2018 May 15;26(9):2381-2391. doi: 10.1016/j.bmc.2018.03.039.
Shaofeng Sun 1,  Zuopeng He 1,  Mindong Huang 1,  Ningning Wang 1,  Zongzhong He 2,  Xiangkai Kong 1,  Jianwen Yao 3
Affiliations

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-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E 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-RafV600E 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.

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