Projects per year
Abstract / Description of output
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.
FingerprintDive into the research topics of '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'. Together they form a unique fingerprint.
- 4 Finished
1/09/15 → 28/02/22
Wright, A., Adams, I., Aligianis, I., Baldock, R., Bickmore, W., Caceres, J., Dorin, J., Dunlop, M., FitzPatrick, D., Haley, C., Hastie, N., Hill, B., Jackson, I., Jackson, A., Kudla, G., Meehan, R., O'Connell, M., Overton, I., Patton, E., Taylor, M., Tenesa, A. & Van Heyningen, V.
1/04/12 → 31/07/13
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Drug Discovery
- Edinburgh Cancer Research Centre
Person: Academic: Research Active