Inhibitors of Ubiquitin Isopeptidases as Pharmaceuticals

For a cell, protein degradation is as essential as protein synthesis. One important intracellular mechanism for protein breakdown is the ubiquitin-proteasome pathway, which functions widely in intracellular protein turnover. In preventing cancer, it is important that inactive tumor suppressor proteins be destroyed to allow for the normally active proteins to elicit their function of inhibiting tumor growth. Defects in this pathway can lead to deregulation of these controls, and thus inhibitors of this pathway represent a strategy for helping the cell maintain a pool of active tumor suppressors. This research shows that specific prostaglandins (?12-prostaglandin J2) and other publicly available molecules (shikoccin, dibenzylideneacetone, and curcumin) contain an ???-unsaturated ketone pharmacophore that can be effective against tumor cells. Since this pharmacophore exists in other molecules, ongoing screening may be highly valuable in identifying novel chemotherapeutics.

*Velcade is a FDA approved anti-cancer drug that acts non-specifically as a proteasome inhibitor. The ubiquitin-isopeptidase (UBP) molecules targeted by this research are an alternative to Velcade�s proteasome inhibition mechanism. Patients who do not respond to Velcade or develop resistance to its effects might respond to UBP inhibitors.
*Inhibitors of UBPs might also be adjunctively combined with more traditional therapies aimed at transcriptional inhibition (azacytidine analogs, topoisomerase inhibitors) or activation (DNA methyltransferase inhibitors) to increase their effectiveness.

Stage of Development
An international patent application PCT/US03/22576 �Novel Inhibitors of Ubiquitin Isopeptidases� has been published (international publication # WO 2004/009023 A2). Ongoing work continues for identification of effective pharmacophores in this novel category of compounds. It is available either for developmental research support or licensing under either exclusive or non-exclusive terms.

Additional Info
Yu MK, Moos PJ, Cassidy P, Wade M, Fitzpatrick FA. �Cyclopentenone prostaglandins of the J series inhibit the ubiquitin isopeptidase activity of the proteasome pathway� J Biol Chem. 276(32): pp. 30366-73 (Aug 10, 2001).

Inventor(s): James Mullally, Francis (Frank) Fitzpatrick, Philip Moos

Type of Offer: Licensing

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