Description of Invention:
The present invention discloses novel pyrazolidinyl compounds that inhibit undesired cell proliferation. The compounds inhibit ubiquitin E1 and can be useful for regulating protein ubiquitination. Specifically, the novel pyrazolidinyl compounds can stabilize p53 and induce apoptosis in mammalian cells through selective inhibition of ubiquitin E1.
Ubiquitin-mediated proteolysis is an important pathway of non-lysosomal protein degradation that controls the timed destruction of a number of cellular regulatory proteins including p53. The ubiquitin pathway leads to the covalent attachment of poly-ubiquitin chains to target substrates which are then degraded by a multi-catalytic proteosome complex.
The compounds can be useful in the treatment of solid and disseminated cancers or other undesired cell proliferation disease or retroviral infections such as HIV.
Applications and Modality:
Treatment of disorders related to ubiquitin E1, such as HIV and viral infections
Compounds are the first general inhibitors of Ubiquitin E1 with broader biological effects than existing proteosome inhibitors
The compounds can serve as a probe to understand the ubiquitin system
Market:
Bortezomib (marketed as Velcade™ by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor approved by the FDA. Severe side effects such as peripheral neuropathy occur in 30% of patients treated with Bortezomib. New drugs targeting proteins in ubiquitination pathway are needed that will have broader efficacy and reduced side effects.
Development Status:
The technology is in the pre-clinical stage of development.
Patent Status:
DHHS Reference No. E-070-2005/0 --
U.S. Provisional Application No. 60/738,242 filed 19 Nov 2005
International Patent Application No. PCT/US2006/0045032 filed 20 Nov 2006, which published as WO 2007/059356 on 19 Jul 2007
U.S. Patent Application No. 12/154,156 filed 20 Nov 2006
Relevant Publication:
A manuscript related to this technology will be available as soon as it is accepted for publication.
Y Yang et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell. 2005 Jun;7(6):547-559. [PubMed abs]
Licensing Status: Available for exclusive and non-exclusive licensing.
Collaborative Research Opportunity:
The National Cancer Institute’s Laboratory of Protein Dynamics and Signaling is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of ubiquitin E1. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.
Portfolios: Cancer
Cancer -Diagnostics-In Vitro-MAb Based Cancer -Diagnostics-In Vitro-Other Cancer -Therapeutics-Biological Response Modifiers-Other Cancer -Diagnostics Cancer -Therapeutics
For Additional Information Please Contact: Surekha Vathyam Ph.D.
Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301/435-4076
Email: vathyams@mail.nih.gov
Fax: 301/402-0220
