Design of Novel Molecules that Modify the Activity of the Transcriptional Coactivator p300/CBP

Inventors: Ronen Marmorstein, Xin Liu, Philip Cole, and Ling Wang

Tech ID: MR07002

Description: Researchers at The Wistar Institute and The Johns Hopkins University have characterized the structure of the histone acetyltransferase (HAT) domain of the p300/CBP transcriptional coactivator. p300/CBP is highly-conserved and is critical for regulating the transcription of a wide range of eukaryotic genes through its HAT activity. Aberrant p300/CBP function, through overexpression, chromosomal translocation or mutation has been linked to a number of diseases including various solid tumors and leukemia, cardiac disease, diabetes, and HIV pathogenesis . The structure of p300/CBP has been determined in complex with a peptide-based inhibitor and the structure suggests a number of key residues that contribute to the chemistry of acetyl transfer by p300/CBP as well as ideas for the structure-based design of small molecule p300/CBP inhibitors. This structure therefore forms a template for designing more specific compounds that are capable of modifying the HAT activity of this transcriptional coactivator.  Using this scaffold, the researchers have already identified specific lead small molecule compounds that are capable of modifying the activity of this target.

Key Words: p300/CBP, histone acetyltransferase, cardiac disease, HIV, diabetes mellitus, cancer therapy, leukemia, rational drug design

Applications and Advantages:A method for designing, screening, and testing small molecule compounds that target the HAT domain of the p300/CBP transcriptional coactivator, using in silico or in vitro methods, is provided.  The researchers have found that while the p300 HAT domain is similar to other HAT structures, it possesses several unique structural characteristics that could be exploited to design p300/CBP-specific effectors. Regulators of p300/CBP could be useful in cancer therapy, treatment of HIV, or a variety of metabolic diseases. These compounds could also be used to augment or correct the effects of mutations associated with disease.

Intellectual Property Status: PCT Application No. PCT/US2008/067477 (WO 2008/157680, published 12/24/2008); U.S. and international applications have been filed.

Licensing Opportunity: Wistar is seeking to collaborate with a corporate partner to use this technology to develop small molecule modulators of p300/CBP. An exclusive license or sponsored research to further develop the technology would be considered.

Contact:

Meryle J. Melnicoff
Director, Business Development
The Wistar Institute
3601 Spruce Street
Room 322
Philadelphia, PA 19104
Phone: (215) 898-0049
Fax: (215) ) 495-6861
melnicoff@wistar.org

Last Updated: Jun-09