Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

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. [Mol Cancer Ther 2009;8(2):324 -32]

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

“…In this latter model, following the guidelines used by clinicians to score response in solid tumors (39), we observed not only stasis but also tumor regression (with a "partial response" in 20-50% of evaluated tumors) and we believe this may be a significant finding in comparison with other latest-generation CDKIs. Several "evolved" CDK2 inhibitors, such as R547 (40), P276-00 (41), AT7519 (42), and AZD5438 (43), are reported to be in late preclinical or clinical testing, but we believe PHA-848125 is unique in possessing the combined properties reported here of good oral bioavailability, capacity to induce tumor regression, and flexibility of treatment scheduling, as shown in the DMBA-induced mammary carcinoma model. Notably, in all preclinical efficacy experiments, PHA-848125 was well tolerated without overt signs of toxicity.…”

AT7519, a Cyclin-Dependent Kinase Inhibitor, Exerts Its Effects by Transcriptional Inhibition in Leukemia Cell Lines and Patient Samples

“…AT7519 was rationally designed with the use of high throughput X-ray crystallography (1), and its activity has been evaluated in preclinical models (2) and a phase I clinical trial in refractory solid tumors (3). Recently, the role of cdks 7, 8, and 9 in the regulation of transcription has been explored (4,5).…”

“…We observed in solid tumor lines that AT7519 is in addition a potent inhibitor of transcription (2). Based on the transcriptional activity of AT7519, we hypothesized that it would promote apoptosis in leukemia cell lines and chronic lymphocytic leukemia (CLL) cells through this mechanism.…”

Cyclin dependent kinases in cancer

“…Interestingly, we have studied the GSK-3β pathway (known to have a crucial role in several signaling cascades relevant to MM biology), in the context of CDK inhibition, exploring the pharmacology of AT7519, a multi-targeted CDK inhibitor, that potently inhibits CDK1, 2, 4, 6, 7, 9. 12,61,62 The drug has shown potent anti-MM activity both in vitro and in vivo. In addition, molecular studies of AT7519 revealed that GSK-3β has a crucial role in AT7519-mediated antimyeloma effect.…”