PUBLICATION

Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines that Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase

Authors
Fraser, C., Dawson, J.C., Dowling, R., Houston, D.R., Weiss, J.T., Munro, A.F., Muir, M., Harrington, L., Webster, S.P., Frame, M.C., Brunton, V.G., Patton, E.E., Carragher, N.O., Unciti-Broceta, A.
ID
ZDB-PUB-160427-2
Date
2016
Source
Journal of medicinal chemistry   59(10): 4697-4710 (Journal)
Registered Authors
Patton, E. Elizabeth
Keywords
none
MeSH Terms
  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology*
  • Breast Neoplasms/drug therapy*
  • Breast Neoplasms/pathology
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Female
  • HCT116 Cells
  • Humans
  • Lateral Line System/drug effects
  • MCF-7 Cells
  • Mice
  • Molecular Structure
  • Neoplasms, Experimental/drug therapy
  • Neoplasms, Experimental/pathology
  • Protein Kinase Inhibitors/chemical synthesis
  • Protein Kinase Inhibitors/chemistry
  • Protein Kinase Inhibitors/pharmacology*
  • Pyrazoles/chemical synthesis
  • Pyrazoles/chemistry
  • Pyrazoles/pharmacology*
  • Pyrimidines/chemical synthesis
  • Pyrimidines/chemistry
  • Pyrimidines/pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Zebrafish
  • src-Family Kinases/antagonists & inhibitors*
  • src-Family Kinases/metabolism
PubMed
27115835 Full text @ J. Med. Chem.
Abstract
Novel pyrazolopyrimidines displaying high potency and selectivity towards SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs towards breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically-distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects and inhibits SRC phosphorylation in tumor xenografts in mice.
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