BACKGROUND Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhance...

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 ...

PURPOSE MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of th...

AT7519 is a potent inhibitor of several cyclin-dependent kinases and is currently in early phase clinical development. Recently, cyclin-dependent kinases 7, 8, and 9 have been shown to regulate transcription through phosphorylation of RNA polymerase II. B-cell lymphoproliferative disorders, including chronic lymphocytic leukemia, rely on the expression of transcripts with a short half-life, suc...

Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils dem...

BACKGROUND AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3...

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-depend...

An unbounded number of events exist beneath the intricacy of each particular hematologic malignancy, prompting the tumor cells into an unrestrained proliferation and invasion. Aberrant expression of cyclin-dependent kinases (CDKs) is one of these events which disrupts regulation of cell cycle and subsequently, results in cancer progression. In this study, we surveyed the repressive impact of mu...

An unbounded number of events exist beneath the intricacy of each particular hematologic malignancy, prompting the tumor cells into an unrestrained proliferation and invasion. Aberrant expression of cyclin-dependent kinases (CDKs) is one of these events which disrupts regulation of cell cycle and subsequently, results in cancer progression. In this study, we surveyed the repressive impact of mu...

The strong storyline behind the critical role of cyclin-dependent kinase (CDK) inhibitor proteinsin natural defense against malignant transformation not only represents a heroic perspective forthese proteins, but also provides a bright future for the application of small molecule inhibitorsof CDKs in the novel cancer treatment strategies. The results of the present study revea...