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1.  Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer 
ACS Medicinal Chemistry Letters  2015;6(8):908-912.
BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
doi:10.1021/acsmedchemlett.5b00173
PMCID: PMC4538445  PMID: 26288692
Prostate cancer; androgen receptor; CRPC; BMS-641988
2.  Hydrogen/Deuterium Exchange Mass Spectrometry Applied to IL-23 Interaction Characteristics: Potential Impact for Therapeutics 
Expert review of proteomics  2015;12(2):159-169.
Interleukin-23 (IL-23) is an important therapeutic target for the treatment of inflammatory diseases. Adnectins are targeted protein therapeutics that are derived from domain III of human fibronectin, and have similar protein scaffold to antibodies. A specific adnectin (Adnectin 2) was identified to bind to IL-23 and compete with IL-23/IL-23R interaction, being a potential protein therapeutic. Hydrogen/deuterium exchange mass spectrometry (HDX MS) and computational methods were applied to probe the binding interactions between IL-23 and Adnectin2 and to determine the correlation between the two orthogonal methods. This review article summarizes the current structural knowledge about Il-23 and it focuses on the applicability of HDX MS to investigate the higher order structure of proteins, which plays an important role for the discovery of new and improved biotherapeutics.
doi:10.1586/14789450.2015.1018897
PMCID: PMC4409866  PMID: 25711416
Interleukins; structure; protein-protein interactions; hydrogen/deuterium exchange; mass spectrometry; protein binding; biotherapeutics
3.  Outcome of a Workshop on Applications of Protein Models in Biomedical Research 
Summary
We describe the proceedings and conclusions from a “Workshop on Applications of Protein Models in Biomedical Research” that was held at University of California at San Francisco on 11 and 12 July, 2008. At the workshop, international scientists involved with structure modeling explored (i) how models are currently used in biomedical research, (ii) what the requirements and challenges for different applications are, and (iii) how the interaction between the computational and experimental research communities could be strengthened to advance the field.
doi:10.1016/j.str.2008.12.014
PMCID: PMC2739730  PMID: 19217386
4.  Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound 
PLoS Genetics  2006;2(4):e57.
We report here on a chemical genetic screen designed to address the mechanism of action of a small molecule. Small molecules that were active in models of urinary incontinence were tested on the nematode Caenorhabditis elegans, and the resulting phenotypes were used as readouts in a genetic screen to identify possible molecular targets. The mutations giving resistance to compound were found to affect members of the RGS protein/G-protein complex. Studies in mammalian systems confirmed that the small molecules inhibit muscarinic G-protein coupled receptor (GPCR) signaling involving G-αq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-αq signaling complex, and define new mutations in both RGS and G-αq, including a unique hypo-adapation allele of G-αq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation.
Synopsis
The authors have utilized Caenorhabditis elegans, and yeast genetics, combined with mammalian tissue and cell culture experiments to investigate the mechanism of action of a unique set of small molecules. These molecules are active in tissue models of urinary incontinence and allow for increased bladder filling. In the course of studying sensitivity and resistance to these compounds, Fitzgerald et al. uncovered novel alleles of RGS and Gq proteins. Further characterization of one such allele identified that its action conferred a hypo-adaptive phenotype on yeast during pheromone signaling assays. Their data as a whole indicate that these small molecules are able to diminish signaling from G-protein coupled receptors (GPCR) downstream of the receptors themselves. Since GPCR signaling is very important in many diseases in humans, the novel mechanism of these compounds may offer new ways to treat human disease.
doi:10.1371/journal.pgen.0020057
PMCID: PMC1440875  PMID: 16683034

Results 1-4 (4)