ZFIN ID: ZDB-PUB-170609-6
From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
Zhang, C.H., Chen, K., Jiao, Y., Li, L.L., Li, Y.P., Zhang, R.J., Zheng, M.W., Zhong, L., Huang, S.Z., Song, C.L., Lin, W.T., Yang, J., Xiang, R., Peng, B., Han, J.H., Lu, G.W., Wei, Y.Q., Yang, S.Y.
Date: 2016
Source: Journal of medicinal chemistry   59: 9788-9805 (Journal)
Registered Authors: Chen, Kai
Keywords: none
MeSH Terms:
  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology*
  • Apoptosis/drug effects
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, SCID
  • Molecular Structure
  • Neoplasms, Experimental/drug therapy
  • Neoplasms, Experimental/pathology
  • Pyrazoles/chemical synthesis
  • Pyrazoles/chemistry
  • Pyrazoles/pharmacology*
  • Pyrimidines/chemical synthesis
  • Pyrimidines/chemistry
  • Pyrimidines/pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Triple Negative Breast Neoplasms/drug therapy*
  • Triple Negative Breast Neoplasms/pathology
  • Tumor Cells, Cultured
  • Zebrafish
PubMed: 27739679 Full text @ J. Med. Chem.
Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.