2. Academic Validation
  3. Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors

  • Bioorg Chem. 2024 Mar:144:107134. doi: 10.1016/j.bioorg.2024.107134.
Ridong Li 1,  Lidong Gong 2,  Jiawei Sun 3,  Zichao Liang 2,  Jianan He 4,  Junjie Huang 4,  Xianling Ning 2,  Huajie Song 2,  Runtao Li 5,  Qiang Zhang 5,  Zhiqiang Lin 6,  Yuxin Yin 7
Affiliations

Affiliations

  • 1 Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: lrd@bjmu.edu.cn.
  • 2 Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
  • 3 Department of Pharmaceutics, College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, PR China.
  • 4 MindRank AI Ltd., Kejiyuan Road, Hangzhou, Zhejiang 310000, PR China.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
  • 6 Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: zhiqiang_lin@bjmu.edu.cn.
  • 7 Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: yinyuxin@hsc.pku.edu.cn.
PMID: 38237389 DOI: 10.1016/j.bioorg.2024.107134
Abstract

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human Cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four Cancer cell lines within concentrations of 1.5 μM. Furthermore, these three compounds displayed higher selectivity of Cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 μM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing Apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK Inhibitor that deserves further optimization to improve its druggability.

Keywords

2,4-Diarylaminopyrimidine; Anti-tumor activity; Dithiocarbamate; FAK inhibitors; Sulfonamide.

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