ZFIN ID: ZDB-PUB-130211-9
Structure-Activity Relationship Studies of Pyrazolo[3,4-d]Pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity Against Acute Myeloid Leukemia (AML) in Vitro and in Vivo
Yang, L.L., Li, G.B., Ma, S., Zou, C., Zhou, S., Sun, Q.Z., Cheng, C., Chen, X., Wang, L.J., Feng, S., Yang, S.Y., and Wei, Y.
Date: 2013
Source: Journal of medicinal chemistry   56(4): 1641-55 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Angiogenesis Inhibitors/chemical synthesis
  • Angiogenesis Inhibitors/chemistry
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents/chemical synthesis*
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Drug Screening Assays, Antitumor
  • Embryo, Nonmammalian/blood supply
  • Embryo, Nonmammalian/drug effects
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy*
  • Leukemia, Myeloid, Acute/pathology
  • Mice
  • Neoplasm Transplantation
  • Phenylurea Compounds
  • Pyrazoles/chemical synthesis*
  • Pyrazoles/chemistry
  • Pyrazoles/metabolism
  • Pyrazoles/pharmacology
  • Pyrimidines/chemical synthesis*
  • Pyrimidines/chemistry
  • Pyrimidines/metabolism
  • Pyrimidines/pharmacology
  • Signal Transduction/drug effects
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Urea/analogs & derivatives*
  • Urea/chemical synthesis
  • Urea/chemistry
  • Urea/metabolism
  • Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
  • Zebrafish
  • fms-Like Tyrosine Kinase 3/antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3/metabolism
PubMed: 23362959 Full text @ J. Med. Chem.

We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and SAR analysis using cell- and transgenic zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable anti-angiogenic effect in transgenic zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin -4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.