Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 10, Pages 4697-4710Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00065
Keywords
-
Categories
Funding
- MRC
- Wellcome Trust [ISSF 2012/13, WT84637]
- Sunergos Innovations
- ERC [294440, 643092 ZF-MEL-CHEMBIO]
- RCUK
- IGMM
- European Research Council (ERC) [294440] Funding Source: European Research Council (ERC)
- Medical Research Council [MC_PC_U127585840, 1201653] Funding Source: researchfish
- MRC [MC_PC_U127585840] Funding Source: UKRI
Ask authors/readers for more resources
Novel pyrazolopyrimidines displaying high potency and selectivity toward 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 toward 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available