[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: rr154z@nih.gov. 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
