2. Academic Validation
  3. Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines

Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines

  • Bioorg Med Chem. 2018 Aug 7;26(14):4179-4186. doi: 10.1016/j.bmc.2018.07.007.
Changyuan Wang 1,  Si Li 1,  Qiang Meng 1,  Xiuli Sun 2,  Hua Li 1,  Xiaohong Shu 1,  Huijun Sun 1,  Kexin Liu 1,  Zhihao Liu 3,  Xiaodong Ma 4
Affiliations

Affiliations

  • 1 College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China.
  • 2 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
  • 3 College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: liuzhihao12399@126.com.
  • 4 College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
PMID: 30006143 DOI: 10.1016/j.bmc.2018.07.007
Abstract

A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent Btk inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest Btk Inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the Btk protein. All these findings provided new clues about the pyrimidine scaffold as an effective Btk Inhibitor for the treatment of B-cell lymphoma.

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