2. Academic Validation
  3. Discovery of Novel Bruton's Tyrosine Kinase (BTK) Inhibitors Bearing a N,9-Diphenyl-9 H-purin-2-amine Scaffold

Discovery of Novel Bruton's Tyrosine Kinase (BTK) Inhibitors Bearing a N,9-Diphenyl-9 H-purin-2-amine Scaffold

  • ACS Med Chem Lett. 2016 Sep 21;7(12):1050-1055. doi: 10.1021/acsmedchemlett.6b00235.
Yang Ge 1,  Yue Jin 1,  Changyuan Wang 1,  Jianbin Zhang 1,  Zeyao Tang 1,  Jinyong Peng 1,  Kexin Liu 1,  Yanxia Li 2,  Youwen Zhou 3,  Xiaodong Ma 1
Affiliations

Affiliations

  • 1 College of Pharmacy, Dalian Medical University , Dalian 116044, P. R. China.
  • 2 Respiratory Department, The First Affiliated Hospital of Dalian Medical University , Dalian 116011, P. R. China.
  • 3 Department of Dermatology and Skin Science, University of British Columbia , Vancouver, BC V5Z 4E8, Canada.
PMID: 27994736 DOI: 10.1021/acsmedchemlett.6b00235
Abstract

Based on the pyrimidine skeleton of EGFRT790M inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective Btk inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of Btk with concentrations of 7.75 and 12.6 μM. The activity of the subject compound as determined by the CCK-8 method and Apoptosis analysis validated that inhibitor 10j is slightly more potent than AVL-292 and ibrutinib. The results of these experimental explorations suggested that 10j could serve as a valuable molecule for control of leukemia pending further developments.

Keywords

BTK inhibitor; Leukemia; activity; purin; synthesis.

Figures