[Federal Register Volume 69, Number 116 (Thursday, June 17, 2004)]
[Notices]
[Page 33926]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-13641]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Identification of a Tricyclic Amino Amide (NSC-644221) Inhibitor of the 
Hypoxic Signaling Pathway

Giovanni Melillo (NCI).
DHHS Reference Nos. E-185-2004/0-US-01 and E-185-2004/1-US-01.
Licensing Contact: George Pipia; 301/435-5560; [email protected].

    This invention describes the identification of a tricyclic (1,4-
dioxane) amino amide with confirmed potent activity in inhibiting HIF-1 
transcriptional activity.
    HIF-1 is a transcription factor and plays an important role in 
adaptation of cancer cells to an hypoxic environment. HIF-1 
significantly increases the ability of cancer cells to survive under 
strenuous conditions. It contributes to the ability of cancer cells to 
migrate and invade surrounding tissue, and is important for the 
formation of new blood vessels that are essential for growth and 
metastasis of cancer cells. Thus HIF-1 mediates survival and spreading 
of cancer cells. Previous studies have shown that HIF-1 is also 
important in human cancers, and therefore, inhibition of HIF-1 activity 
is contemplated in the field as a therapy for cancer patients.
    The inventors, using a cell-based high throughput screen, 
identified a new compound, NSC-644221, with potent inhibitory activity 
of the HIF-1 pathway. The compound inhibits expression of HIF-1 and 
reduces its accumulation in the cell. This compound also inhibits 
expression of endogenous genes that are under control of HIF-1, such as 
Vascular Endothelial Growth Factor (VEGF) that is essential for the 
formation of new blood vessels. The NIH inventors currently are testing 
the compound in angiogenesis assays and are starting preclinical 
studies of the compound using animal cancer models.

SH2 Domain Binding Inhibitors

Terrence R. Burke, Jr., Zhen-Dan Shi, Kyeong Lee (NCI).
U.S. Provisional Application No. 60/504,241 filed 18 Sep 2003 (DHHS 
Reference No. E-315-2003/0-US-01).
Licensing Contact: George Pipia; 301/435-5560; [email protected].

    The present invention provides for ultra-potent Grb2 SH2 domain-
binding compounds, or a pharmaceutically acceptable salt thereof. The 
compounds of the present invention represent tetrapeptide mimetics 
whose conformation is constrained through macrocyclization. Low 
picomolar binding affinity is achieved in in vitro Grb2 SH2 domain 
binding assays. Addition of covered agent to the extracellular media of 
erbB-2 over-expressing breast cancer cells at low nanomolar 
concentrations results in effective intracellular blockade of Grb2 
association with activated cytoplasmic erbB-2 tyrosine kinase. 
Antimitogenic effects are observed in erbB-2-dependent breast cancer 
cells in culture at sub-micromolar concentrations. The present 
invention further provides a pharmaceutical composition comprising a 
pharmaceutically or pharmacologically acceptable carrier and a compound 
of the present invention. The present invention also provides a method 
for inhibiting an SH2 domain from binding with a phosphoproteins 
comprising contacting an SH2 domain with a compound of the present 
invention. The present invention also provides a method of preventing 
or treating a disease state or condition by the use of the compound. 
While the invention has been described and disclosed below in 
connection with certain embodiments and procedures, it is not intended 
to limit the invention to those specific embodiments. Rather it is 
intended to cover all such alternative embodiments and modifications as 
fall within the spirit and scope of the invention.
    This research is described, in part, in: Z. Shi et al., ``A novel 
macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 
domain-binding affinity,'' Biochem. Biophys. Res. Commun. (2003 Oct 17) 
310(2):378-383, doi:10.1016/j.bbrc.2003.09.029; Z. Shi et al., 
``Synthesis of a 5-methylindolyl-containing macrocycle that displays 
ultrapotent Grb2 SH2 domain-binding affinity,'' J. Med. Chem. (2004 Feb 
12) 47(4):788-791, doi:10.1021/jm030440b.

    Dated: June 4, 2004.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 04-13641 Filed 6-16-04; 8:45 am]
BILLING CODE 4140-01-P