Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

Rathos

Molecular Cancer Therapeutics

et al. 2007

117

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC 50 below 250 nmol/L. In this report, we have described the properties of one of the best compound,

Section: Introductionmentioning

confidence: 99%

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Rathos

Molecular Cancer Therapeutics

et al. 2007

117

Molecular Cancer Therapeutics

“…One of these compounds, R-roscovitine (13), is now undergoing evaluation in phase II clinical trials. In addition, more selective inhibitors of CDK2 are being investigated (14,15).…”

Section: Introductionmentioning

confidence: 99%

The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor

Byth

Geh

Forder

et al. 2006

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. IC 50 s 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 G 1 -, S-, and G 2 -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. [Mol Cancer Ther 2006;5(3):655 -64]

“…4A). In addition, a selective CDK2 inhibitor, Bristol-Myers Squibb aminothiazole compound 25 25,31 also promoted a rapid loading of MCM proteins onto chromatin (RIPA350 extracted, Fig. 4B).…”

mentioning

confidence: 99%

Human CDK2 Inhibition Modifies the Dynamics of Chromatin-Bound Minichromosome Maintenance Complex and Replication Protein A

Zhu¹,

Ishimi²,

Tanudji³

et al. 2005

Cell Cycle

Previously published as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=1975 KEY WORDSCDK2, MCM4, RPA, ATR, re-replication, MCM2, checkpoint ACKNOWLEDGEMENTSWe thank all members of the Lead Identification Laboratory for initial studies of CDK2 inhibitor; members of Oncology group in the Department of Discovery Research for helpful discussions; and Scott Frank, Larry L'Italien, Loren Russell, Xiao Min Schebye for CDK2, CDK1, and cyclin E siRNAs validation and retroviral siRNA expression system design. DNAX Research, Inc. is a fully owned subsidiary of Schering-Plough Research Institute. Report Human CDK2 Inhibition Modifies the Dynamics of Chromatin-Bound Minichromosome Maintenance Complex and Replication Protein A ABSTRACTMinichromosome maintenance (MCM) proteins form a complex and possess helicase activity to unwind the DNA duplex and establish a replication fork. To assure that origins only fire once per cell cycle, the MCM complex is removed from chromatin and inactivated as cells exit S phase. In this report, we demonstrate that CDK2 depletion in human cells leads to an overall phosphorylation defect at mitosis with increased re-replication, correlated with the accumulation of chromatin-bound MCM proteins. We show that CDK2 suppression results in decreased MCM4 phosphorylation at multiple serine and threonine sites. In addition, CDK2 inhibition induces an increase in chromatin-bound replication protein A (RPA) which should bind to single-stranded DNA regions, possibly establishing a replication intermediate that activates the ATR cascade. Finally, we observe that loss of CDK2 function in G 1 delays replication initiation while it promotes re-replication in G 2 /M. Thus, by modulating the phospho-status of MCM4 and regulating origin firing, S phase CDK2 appears to be an integrated component of cellular machinery required for temporally controlling replication activity and maintaining genomic stability.