The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor.
Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK inhibitors. Here, we describe data on the in vitro biological activities of one of these compounds, AZ703. The selectivity profile of AZ703 was investigated in kinase assays against a range of CDK enzymes as well as a panel of protein kinases in vitro. IC50s were assessed against different tumor cell lines in vitro. The mechanism of action of AZ703 was determined by observing changes in phosphorylation of CDK substrates and cell cycle effects on tumor and normal cells. In vitro studies revealed that AZ703 is a selective inhibitor of CDK1 and CDK2 and displays a mode of action consistent with the induction of G1-, S-, and G2-M-phase arrest. AZ703 also showed potent antiproliferative activity across a wide range of tumor cell lines in vitro. Moreover, AZ703 induced reversible blockade of normal cells while causing tumor cells to undergo apoptosis. We have identified AZ703 as a novel selective imidazo[1,2-a]pyridine CDK inhibitor that shows promising antitumor properties in vitro.
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Kate.Byth@astrazeneca.com
Kate F
KF
Byth
Catherine
C
Geh
Cheryl L
CL
Forder
Sandra E
SE
Oakes
Andrew P
AP
Thomas
D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*
C507945:AZ703 compound; D007093:Imidazoles; D011725:Pyridines; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2