ActivX Biosciences Announces Publication of Papers on Activity-Based Chemical Probes

August 8, 2002

LA JOLLA, California, August 8, 2002 . ActivX Biosciences, Inc., a privately held biotechnology company developing "chemoproteomics" technologies for drug discovery, announced today the publication in two prestigious journals of papers on the design and use of activity-based chemical probes licensed exclusively by the Company from The Scripps Research Institute.   

A paper entitled "Enzyme Activity Profiles of the Secreted and Membrane Proteome Predict Cancer Invasiveness" from the laboratory of Scripps faculty member Benjamin Cravatt, Ph.D., a co-founder, collaborator and Scientific Advisory Board member of ActivX, appears in the July 30, 2002 issue of the Proceedings of the National Academy of Sciences.  A second article, entitled " Proteomic Profiling of Mechanistically Distinct Enzyme Classes Using a Common Chemotype" authored by Dr. Cravatt, ActivX Scientific Advisory Board member Eric Sorensen, Ph.D. and colleagues, reports on the use of combinatorial approaches to generate activity-based chemical probes for interrogating biological samples, and appears in the August 2002 issue of Nature Biotechnology. 

Cancer Profiling Using Activity-Based Chemical Probes

As reported in the Proceedings of the National Academy of Sciences, Cravatt and colleagues examined a panel of tumor cell lines with activity-based chemical probes able to detect active members of the serine hydrolase enzyme superfamily, including proteases, lipases and esterases.  They showed that tumor cell lines of different origins, e.g., breast carcinomas and melanomas, could be distinguished by the activity profiles of different cellular fractions, including membrane-associated, cell-associated and secreted proteins.  Further, they demonstrated that in cell lines representing highly invasive tumors, there was a common activity profile regardless of the original tissue type from which the tumor resulted, suggesting common features among invasive tumors and potentially common ways of identifying and treating them.  Finally, several novel candidate protein drug targets and biomarkers were identified. 

"This is an excellent example of the direct impact of activity-based proteomics on the drug discovery process", said John W. Kozarich, Ph.D., President, Chief Executive Officer and Chief Scientific Officer of ActivX.  "The identification of novel, druggable targets for pharmaceutical research remains a challenge despite the completion of the sequence of the human genome.  Large numbers of genes in the genome are completely unexplored, and there are important discoveries to be made by integrating the type of data resulting from profiling studies like those conducted by Dr. Cravatt with genomic and other information.  Direct functional characterization of proteins and revealing their involvement in specific disease processes are key aspects of ActivX's chemoproteomic drug target and biomarker discovery capabilities." 

Combinatorially Derived Activity-Based Chemical Probes

As reported in Nature Biotechnology, the research conducted by Cravatt and Sorenson involved the combinatorial synthesis of a set of activity-based probes built on a sulfonate ester scaffold.  Activity-based probes react with members of specific protein classes in an activity dependent manner, i.e., they only react with active proteins, and thus afford researchers the ability to distinguish active from inactive proteins in biological samples, a distinction that can't be made using gene chips or other proteomic techniques and is very important for drug discovery.  When the probes were evaluated in a biological sample (heart tissue) they were shown to label six mechanistically distinct enzyme classes.  Interestingly, the different probes had relatively little overlap for the enzyme classes with which they interacted, suggesting that the development of probes for diverse protein families could result from closely related chemical structures.   In addition, a particular protein, a type of glutathione-S-transferase, was shown to be significantly up-regulated in breast cancer cell lines, demonstrating how these probes are used for drug target or biomarker discovery. 

In a News and Views commentary on the article appearing in the same issue of Nature Biotechnology, John Gerlt, Ph.D., professor and head of the Department of Biochemistry at the University of Illinois, Urbana-Champaign, said, "Activity-based profiling is an attractive and important strategy for identifying functionally active participants in biological processes in the presence of "inactive" or "spectator" proteins.  Neither transcriptional profiling nor identification of the members of the proteome can provide this information."

"The ability to rapidly and systematically generate protein family-selective chemical affinity probes is very powerful", said Kozarich.  "In combination with ActivX's high throughput protein analysis and identification capability, we expect to expand our collection of novel drug targets and biomarkers.  We are employing our chemoproteomics platform not only in target discovery, but also lead optimization, selectivity profiling and toxicity analysis."  

About ActivX Biosciences

ActivX Biosciences, Inc., (www.activx.com), a privately held biotechnology company in La Jolla, California, is a pioneer in the field of activity-based proteomics, the identification and analysis of active proteins key in both normal and disease situations. By focusing on protein activity, ActivX addresses disease mechanisms directly, in contrast to standard genomics and proteomics techniques. ActivX technology includes novel chemical probes integrated with a high-throughput protein analysis platform to rapidly interrogate the activities of proteins in all ranges of abundance in any biological sample, a process it has termed "chemoproteomics". ActivX and its partners are using its proprietary technology to solve critical problems in drug discovery and development, including identifying novel drug targets and biomarkers, guiding the medicinal chemistry optimization of lead compounds through profiling and selectivity analysis against active proteins in target cells and tissues, and assessing efficacy and toxicity for candidate and established drugs.

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