[Federal Register Volume 64, Number 163 (Tuesday, August 24, 1999)]
[Notices]
[Pages 46206-46207]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21889]


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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 agencies 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 contacting Richard U. 
Rodriguez, M.B.A., Technology Licensing Specialist, Office of 
Technology Transfer, National Institutes of Health, 6011 Executive 
Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/
496-7056 ext. 287; fax: 301/402-0220; e-mail: [email protected]. A signed 
Confidential Disclosure Agreement will be required to receive copies of 
the patent applications.

Peptides and Their Utility in Modulation of Behavior of Cells 
Expressing 31 Integrins

David D. Roberts, Henry C. Krutzsch (NCI)
    DHHS Reference No. E-169-99/0 filed 15 Jul 1999

    The present invention relates generally to peptides that bind to or 
are recognized by 31 integrins and in particular, to 
pharmaceutical compositions containing and methods of using said 
peptides to inhibit or promote various functions of cells that express 
31 integrins.
    Integrins are transmembrane , 1-heterodimer 
receptors expressed on a wide variety of cells which are involved in 
extracellular matrix (ECM) interactions. Experimental data has shown 
that the ECM can affect gene expression and that this altered gene 
expression can change the composition of the ECM. A bi-directional 
exchange of information between cells and their surrounding matrix is 
therefore taking place and because of this communication, integrins can 
control cell growth, motility, differentiation and survival. Defects in 
the regulation of these processes can result in many disease states, 
such as inheritable developmental disorders, defective wound repair, 
hemotological disorders, cardiovascular diseases, immunological 
disorders, neurodegenerative diseases and cancer initiation, invasion 
and metastasis. The disclosed peptides have been shown to inhibit 
angiogenesis, cell adhesion and proliferation and wound repair when 
administered in a soluble

[[Page 46207]]

form; however, when the same peptides are immobilized on a substratum, 
they promote adhesion and proliferation of endothelial cells. Thus by 
controlling the conditions, these peptides can be used to generate 
specific responses. Specific applications for the peptides include the 
treatment of angiogenesis-mediated diseases, production of vascular 
grafts and artificial blood vessels.

Redox-Stable, Non-Phosphorylated Cyclic Peptide Inhibitors of SH2 
Domain Binding to Target Protein, Conjugates Thereof, Compositions 
and Methods of Synthesis and Use

Serial No. 60/137,187 filed 02 Jun 1999
    Peter Roller, Ya-Qiu Long, Feng-Di Lung, Charles R. King (NCI)

    The present invention is predicated on the surprising and 
unexpected discovery of non-phoshorylated cyclic peptide inhibitors of 
binding SH2 domains in proteins comprising SH2 domains to target 
proteins which not only are redox-stable in vivo but have unprecedented 
specific binding affinities.
    Src homology-2 (SH2) domains selectively bind to phosphotyrosyl 
(pTyr)-containing regions of target proteins. SH2 binding can modulate: 
c-src activity; substrate specificity for c-abl proto-oncoproteins; and 
the transduction of signals initiated by growth factor receptors and 
cellular attach systems. The SH2 domain of growth factor receptor-bound 
protein (Grb2) is a specific example which contains one SH2 domain and 
two src homology-3 (SH3) domains. The prevention of Grb2-mediated 
multi-protein assemblies is considered a promising therapeutic target 
for the development of antiproliferative agents directed to cells that 
over-express growth factor receptors. Previously identified SH2-
inhibitors have detectable activity, but their binding affinities are 
substantially lower than natural ligands. A need therefore exists for 
more efficient and stable inhibitors, and the technology herein 
disclosed provides for such inhibitors. Additionally, the technology 
offers the possibility of conjugates comprising a compound (SH2 
inhibitor) and a carrier agent, i.e., signal peptides, antennapedia 
peptides, or lipofectin. Suitable targets would preferably include, but 
not necessarily be limited to: growth factor receptors, such as EGFR; 
morphology determining proxies, such as FAK; a cellular attachment 
protein; a proto-oncoprotein; an oncoprotein, such as BCR-abl; or a 
mitogen-activated protein (MAP). In one application of this method, 
inhibition of the binding of a target protein by an SH2 domain in a 
protein comprising an SH2 domain prevents cancer, in particular, breast 
cancer. Administration of the SH2-inhibitor/SH2-conjugate can be 
accompanied by an anti-cancer agent such as a chemotherapeutic agent, a 
cytotoxic agent or its prodrug, radiation and/or a radioactive isotope.

Phenylalanine Derivatives

T. Burke et al. (NCI)
    Serial No. 60/126,047 filed 23 Mar 1999

    The present invention relates to novel phenylalanine derivatives, 
compositions and methods of using said derivatives to inhibit SH2 
domain binding with a phosphoprotein. Additionally, the invention 
provides precursors suitable for preparing these phenylalanine 
derivatives.
    The therapy and prophylaxis of proliferative diseases such as 
cancer, autoimmune disorders and hyperproliferative skin disorders can 
involve signal transduction. These signal-pathways are critical to 
normal cellular homeostasis and are necessary processes for relaying 
extracellular messages from various sources, e.g., growth factors, 
hormones or neurotransmitters, via receptors to the interior of the 
cell. Protein-tyrosine kinases are integral participants of many of 
these pathways, and they are responsible for the phosphorylation of 
specific tyrosine residues to form tyrosine phosphorylated residues. 
These pathways can involve complex networks which contain proteins with 
specific amino acid sequences called ``Src-homology 2'' (SH2) domains. 
Malfunctions in these protein-tyrosine phosphorylations through 
tyrosine kinase overexpression or deregulation, can manifest a variety 
of oncogenic and proliferative disorders. SH2 domain containing 
proteins that play roles in cellular signaling and transformation 
include, but are not limited to: Src, Lck, Ras GTPase-activating 
protein, Phospholipase C, PI-3 kinase, Grb2, BCR Abl and Tyk2. Central 
to the binding of SH2 domains with phosphotyrosine (pTyr)-containing 
ligands is the interaction of a doubly ionized pTyr phosphate with two 
highly conserved arginine residues. These interactions are critical, 
and binding is usually lost by removal of the phosphate group. While 
the pTyr-pharmacophore therefore plays a dominant role in SH2 domain-
ligand interactions, pTyr residues are not suitable components of 
inhibitors intended for in vivo application, due to the enzymatic 
lability of the phosphate ester bond and the poor cellular penetration 
of the doubly ionized phosphate species. Therefore, a need exists for 
non phosphate containing compounds that can mimic the structural 
interactions of phosphotyrosyl residues within SH2 domain pTyr-binding 
sites, and in so doing disrupt the interactions between SH2 domains of 
proteins, e.g., Grb2, and proteins with phosphorylated moieties. The 
disclosed invention provides viable candidates for these compounds and 
could provide for the development of therapeutic agents for the 
treatment of proliferative diseases or conditions as well as relevant 
diagnostic or testing procedures.

    Dated: August 17, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 99-21889 Filed 8-23-99; 8:45 am]
BILLING CODE 4140-01-M