Novel small-molecule inhibitors of hepatitis C virus entry block viral spread and promote viral clearance in cell culture.

Combinations of direct-acting anti-virals offer the potential to improve the efficacy, tolerability and duration of the current treatment regimen for hepatitis C virus (HCV) infection. Viral entry represents a distinct therapeutic target that has been validated clinically for a number of pathogenic viruses. To discover novel inhibitors of HCV entry, we conducted a high throughput screen of a proprietary small-molecule compound library using HCV pseudoviral particle (HCVpp) technology.

Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibitors.

The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition.

Chemical genetic approaches to kinase drug discovery.

Chemical genetics is an important approach in biological research that utilizes small molecules to study protein function. In the context of kinase drug discovery, chemical genetics has broad applications in identifying and validating targets, demonstrating the druggability of a target and providing potential kinase inhibitor leads for further optimization. The successful application of this approach demands that the small-molecule kinase inhibitors used achieve a desired potency and selectivity.

The Ste20 kinase MST4 plays a role in prostate cancer progression.

MST4, a member of the Sterile 20 serine/threonine kinase family, was found to be expressed in prostate carcinoma tumor samples and cell lines. In addition, expression levels appeared to correlate with tumorigenicity and androgen receptor status of the cells. Ectopic expression of wild-type and kinase-inactive MST4 was used to alter cellular MST4 activity levels in three widely studied human prostate tumor cell lines: LNCaP, DU 145, and PC-3.