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

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

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.

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