N-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors

  • ACS Med Chem Lett. 2015 Mar 18;6(5):543-7. doi: 10.1021/acsmedchemlett.5b00039.
Yingjun Li  1 ,  Huimin Cheng  2 ,  Zhang Zhang  3 ,  Xiaoxi Zhuang  2 ,  Jinfeng Luo  2 ,  Huoyou Long  2 ,  Yang Zhou  1 ,  Yong Xu  2 ,  Rana Taghipouran  4 ,  Dan Li  4 ,  Adam Patterson  5 ,  Jeff Smaill  5 ,  Zhengchao Tu  2 ,  Donghai Wu  2 ,  Xiaomei Ren  2 ,  Ke Ding  2
Affiliations
  • 1. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China ; University of Chinese Academy of Sciences , #19 Yuquan Road, Beijing 100049, China.
  • 2. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 3. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China ; Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University , #601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4. Auckland Cancer Society Research Centre and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland , #92019 Private Bag, Auckland 1142, New Zealand.
  • 5. Auckland Cancer Society Research Centre and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland , #92019 Private Bag, Auckland 1142, New Zealand ; Auckland Cancer Society Research Centre and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland , #92019 Private Bag, Auckland 1142, New Zealand.
PMID: 26005530 DOI: 10.1021/acsmedchemlett.5b00039
Abstract

A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferation of a panel of human Cancer cell lines and patient-derived melanoma cells with B-Raf(V600E) mutation while being significantly less potent to the cells with B-Raf(WT). The compounds also display favorable pharmacokinetic properties with a preferred example (3s) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-Raf(V600E) mutated Colo205 human colorectal Cancer cells, supporting it as a promising lead compound for further Anticancer drug discovery.

Keywords
B-Raf; colon cancer; kinase inhibitor; melanoma; targeted therapy.