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.
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.
Craig
C
Fraser
John C
JC
Dawson
Reece
R
Dowling
Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh , Edinburgh EH9 3BF, United Kingdom.
Douglas R
DR
Houston
Jason T
JT
Weiss
Alison F
AF
Munro
Morwenna
M
Muir
Faculty of Medicine, University of Montreal, Institute for Research in Immunology and Cancer, Chemin de Polytechnique , Montreal, Quebec H3T 1J4, Canada.
Lea
L
Harrington
University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh , Edinburgh EH16 4TJ, United Kingdom.
Scott P
SP
Webster
Margaret C
MC
Frame
Valerie G
VG
Brunton
E Elizabeth
EE
Patton
Neil O
NO
Carragher
Asier
A
Unciti-Broceta
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D053403:Lateral Line System / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D015027:Zebrafish; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases