Method of Screening compounds that Antagonize HAUSP

Web Published:

Princeton University Invention # 2174 


Cancer is one of the most debilitating diseases affecting mankind. More than 600 thousand patients die of cancer in the United States. Oncogenesis is inhibited by the tumor suppressor genes and accelerated by oncogenes. p53 is one of the most important tumor suppressor proteins and is inactivated in nearly all cases of cancer. In approximately half of all cancer cases, p53 is inactivated by mutation; in the other half of all cancer cases, wild-type p53 is inactivated by accelerated degradation or mis-localization, thus unable to perform its function. MDM2 is an oncoprotein that actively ubiquinates p53, leading to its degradation. MDM2 also ubigquinates itself, thus resulting in its own degradation. Restoration of p53 function in cancer patients constitutes an important and effective therapeutic method.


HAUSP is a member of the UBP family of deubiquinating enzymes and selectively targets MDM2 and p53 for deubiquination, hence rescuing both proteins from degradation. The specific deubiquination relies on the specific binding of MDM2 and p53 by HAUSP.


Researchers at Princeton University have discovered that HAUSP exhibits a much higher binding affinity for MDM2 than for p53, implying that MDM2 is a bona fide substrate for HAUSP in cells. More importantly, the group at Princeton has discovered that both MDM2 and p53 bind to the same surface pocket in the amino-terminal TRAF-like domain of HAUSP in a mutually exclusive manner.  The binding element from MDM2 or p53 is a short peptide composed of no more than 6 amino acids. In addition, a number of crystal structures on HAUSP, including the catalytic core domain, the catalytic core domain bound to ubiquitin aldehyde, the N-terminal TRAF-like domain, the N-terminal TRAF-like domain bound to MDM2 peptide, the N-terminal TRAF-like domain bound to p53 peptide, and the combined TRAF-like and catalytic core domain have been determined at Princeton.  These structures reveal important insights on inhibitor screening. In particular, the TRAF-like domain contains a surface groove that is responsible for binding to the MDM2 or p53 peptide. The catalytic core domain contains a papain-like active site. The carboxy-terminus of ubiquitin is specifically coordinated by a surface cleft in the catalytic core domain.


These novel findings immediately identify methods for the screening of anti-HAUSP compounds that will serve to stabilize p53 protein by destabilizing the human MDM2 protein.


The first method involves screening for compounds that bind to the surface groove of the TRAF-like domain. These compounds will prevent the specific recognition for MDM2 by HAUSP, hence accelerating the degradation of MDM2. The second method involves screening for compounds that bind to the surface cleft of the catalytic core domain, which normally coordinates the carboxy-terminus of ubiquitin. These compounds will interfere with the deubiquinating activity of HAUSP. The third method involves screening for compounds that directly bind to the active site of HAUSP, hence suppressing its catalytic activity.



Princeton is currently seeking industrial collaboration to commercialize this technology. Patent protection is pending.




HU,M., Li,P., Li,M., Li,W., Yao,T., Wu,J., Gu,W., Cohen,R., Shi,Y., December 27, 2002, Crystal Structure of a UBP-Family Deubiquinationg Enzyme in Isolation and in Complex with Ubiquitin Aldehyde, Cell, , Vol. 111, 1041-1054.


Structural Basis of Competitive Recognition of p53 and MDM2 by HAUSP/USP7, Hu,M., Gu,L., Jeffrey,P., Shi,Y., Pending Publication



For more information on Princeton University invention # 05-2174 contact:


                        Laurie Tzodikov

                        Office of Technology Licensing and Intellectual Property

                        Princeton University

                        4 New South Building

                        Princeton, NJ 08544-0036

                        (609) 258-7256

                        (609) 258-1159 fax


Patent Information:
For Information, Contact:
Laurie Tzodikov
Licensing Associates
Princeton University
Yigong Shi