Summary Background: Chemotherapeutic DNA-binding compounds exert their effects, in part, by preventing DNA synthesis and initiating events that leads to apoptotic death. Despite the excellent antiproliferative activity of these compounds, though, elucidating their particular modes of action (i.e. their biological targets) has been difficult. Given this uncertainty, there is a high demand for the development of assays that can identify these essential drug effectors.
Novel Technology: A novel assay for identifying biological targets of DNA binding agents. The platform includes a polynucleotide/DNA binding agent binary complex fused to a solid support such as a resin. It can be used to locate by affinity chromatography a biological target in a cell lysate, extraceullar fluid, serum, plasma, blood or any other solution or suspension thought to contain the biological target. In one example, the assay was used to discover GAPDH as a potential target for Saframycin A analogues, an antiproliferative agent believed to function by covalently modifying duplex DNA. This is the first time that GAPDH has been identified as a potential target for chemotherapeutic intervention, which is all the more intriguing in light of recent evidence of a role for GAPDH as a key transcriptional coactivator necessary for entry into S phase. This platform represents a next-generation method for identification of novel chemotherapeutic agents.
Applications Advantages: This next-generation DNA-affinity linked assay is compatible with all chemical compounds and biological targets that interact with duplex DNA. By elucidating the biological targets of current DNA binding agents, the assay may lead to the discovery of better pharmaceutical agents with similar modes of action. The first in class assay is also amenable to high throughput screening techniques-including robotics, combinatorial chemistry, microfluidics, and computer analysis. For example, a collection of compounds (combinatorial library) or a historical collection of compounds of a pharmaceutical company may be used to screen for potential effectors.
Commercial Applications: This technology is an excellent candidate to be provided as a kit with materials ready to perform the assay. The kit may include polynucleotides, affinity resins, chemical compounds with known targets or mechanism of action, as well as buffers, reagents, purified proteins, antibodies, cell lysates, or the like. The assay can be used as a tool in either industry or an academic research lab to discover agents and biological effectors for the treatment of cancer.
Market: The market for this technology is large because it has the potential to be used at any research laboratory (industrial or academic) in the world. Furthermore, the number of candidate DNA-binding compounds to be used in this assay spans an endless and broad spectrum of species, from plants to marine animals. Moreover, the capabilities of synthetic chemists to generate analogs and intermediates only add to this number.
Chengguo Xing, Jacob R. LaPorte, Joseph K. Barbay and Andrew G. Myers. Identification of GAPDH as a Protein Target of the Saframycin Class of Natural Antiproliferative Agents. Proc. Natl. Acad. Sci. U.S.A 2004, 101, 5862
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