2. Academic Validation
  3. Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents

Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents

  • Eur J Med Chem. 2021 Nov 5:223:113670. doi: 10.1016/j.ejmech.2021.113670.
Hanyi Tan 1,  Yue Liu 1,  Chaochao Gong 1,  Jiawei Zhang 1,  Jian Huang 2,  Qian Zhang 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: jianhuang@sjtu.edu.cn.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: zhangqian511@shmu.edu.cn.
PMID: 34214842 DOI: 10.1016/j.ejmech.2021.113670
Abstract

Focal adhesion kinase (FAK) is a ubiquitous intracellular non-receptor tyrosine kinase, which is involved in multiple cellular functions, including cell adhesion, migration, invasion, survival, and angiogenesis. In this study, a series of 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized according to the E-pharmacophores generated by docking a library of 667 fragments into the ATP pocket of the co-crystal complex of FAK and PF-562271 (PDB ID: 3BZ3). The 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine derivatives demonstrated excellent activity against FAK and the cell lines SMMC7721 and YY8103. 2-((2-((3-(Acetamidomethyl)phenyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylbenzamide (16c) was selected for further bioactivity evaluations in vivo, including preliminary pharmacokinetic profiling in rats and toxicity assays in mice, and tumor growth inhibition studies in a xenograft tumor model. The results showed that 16c did not affect the body weight gain of the Animals up to a dose of 200 mg/kg, and significantly inhibited tumor growth with a tumor growth inhibition rate of 78.6% compared with the negative control group. Furthermore, phosphoantibody array analyses of a sample of the tumor suggested that 16c inhibited the malignant proliferation of hepatocellular carcinoma (HCC) cells through decreasing the phosphorylation in the FAK cascade.

Keywords

5-Fluoro-7H-pyrrolo[2,3-d]pyrimidine derivatives; Focal adhesion kinase (FAK); Hepatocellular carcinoma; Small molecule inhibitors.

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