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.
Citation
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. (2016) 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. Journal of medicinal chemistry. 59(10):4697-4710.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping