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
- Authors
- 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.
- ID
- ZDB-PUB-130211-9
- 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.