Abstract
Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients.
Highlights
Progression through the various phases of the eukaryotic cell cycle has been shown to be critically dependent on a family of proteins known as cyclin-dependent kinases (CDK) and their cognate regulatory partners termed cyclins
An integrated crystallography-based approach was employed for the identification of low molecular weight fragments that bound CDK2 with high efficiency
The inhibition of CDK1 by AT7519 is competitive with ATP, with a Ki value of 38 nmol/L. This observation is consistent with the X-ray structure of a complex of CDK2 and AT7519, confirming that AT7519 binds within the active site cleft of the enzyme overlapping with the ATPbinding site [31]
Summary
Progression through the various phases of the eukaryotic cell cycle has been shown to be critically dependent on a family of proteins known as cyclin-dependent kinases (CDK) and their cognate regulatory partners termed cyclins (reviewed in refs. 1, 2). Progression through the various phases of the eukaryotic cell cycle has been shown to be critically dependent on a family of proteins known as cyclin-dependent kinases (CDK) and their cognate regulatory partners termed cyclins As manifested in cancer, can often be attributed to loss of correct cell cycle control CDK2/cyclin E, CDK4/cyclin D, and CDK6/cyclin D primarily regulate progression from G1 to S phase of the cell cycle. CDK2/cyclin A and CDK1/cyclin A primarily function during S phase and control progression through G2. CDK2/cyclin E plays a role in the p53-mediated DNA damage response pathway and in gene regulation via c-Myc. affecting CDK1 and CDK2 activity may affect cell growth and survival via several mechanisms [11, 12]
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