Angstrom Pharmaceuticals, Inc.

Agouron Pharmaceuticals, Inc.

Terence R Jones

Andrew P Mazar

Michael D Varney

Stephen Evan Webber

Ted Michael Bleckman

John Attard

David N Haney

Janos Varga

Cynthia Louise Palmer

Judith P Deal

Gifford P Marzoni

A peptide compound having the sequence Lys-Pro-Ser-Ser-Pro-Pro-Glu-Glu [SEQ ID NO:2] or a substitution variant, addition variant or other chemical derivative thereof inhibits cell invasion, endothelial tube formation or angiogenesis in vitro. A number of substitution variants and addition variants of this peptide, preferably capped at the N- and C-termini, as well as peptidomimetic derivatives, are useful for treating diseases and conditions mediated by undesired and uncontrolled cell invasion and/or angiogenesis. Pharmaceutical compositions comprising the above peptides and derivatives are administered to subjects in need of such treatment in a dosage sufficient to inhibit invasion and/or angiogenesis. The disclosed compositions and methods are particularly useful for suppressing the growth and metastasis of tumors.

Anti-invasive and anti-angiogenic compositions

A uPAR-targeting protein or peptide is diagnostically or therapeutically labeled and used in methods of diagnosis of therapy. The labeled protein or peptide preferably has the following properties: it comprises at least 38 amino acid residues, including residues 13-30 of the uPAR-binding site of uPA; competes with labeled DFP-uPA for binding to a cell or molecule that has a binding site for uPA, and has an ICvalue of about 10 nM or less; and is not a fusion protein wherein the uPA peptide is fused to another non-uPA protein or peptide. Preferred molecules are uPA, scuPA, tcuPA, an N-terminal fragment of uPA, residues 1-135, an N-terminal fragment of uPA, residues 1-143, an N-terminal fragment of uPA, residues 1-43; or an N-terminal fragment of uPA, residues 4-43. Detectable labels include a radionuclide, a PET-imageable agent, an MRI-imageable agent, a fluorescer, a fluorogen, a chromophore, a chromogen, a phosphorescer, a chemiluminescer or a bioluminescer. The disclosed methods are used to inhibit cell migration, cell invasion, cell proliferation or angiogenesis, or to induce apoptosis, preferably in the treatment of a subject having a disease or condition associated with undesired cell migration, invasion, proliferation or angiogenesis.

Diagnostic probes and therapeutics targeting uPA and uPAR

A peptide compound having the sequence Lys-Pro-Ser-Ser-Pro-Pro-Glu-Glu &lsqb;SEQ ID NO:2&rsqb; or a substitution variant, addition variant or other chemical derivative thereof inhibits cell invasion, endothelial tube formation or angiogenesis in vitro. A number of substitution variants and addition variants of this peptide, preferably capped at the N- and C-termini, as well as peptidomimetic derivatives, are useful for treating diseases and conditions mediated by undesired and uncontrolled cell invasion and/or angiogenesis. Pharmaceutical compositions comprising the above peptides and derivatives are administered to subjects in need of such treatment in a dosage sufficient to inhibit invasion and/or angiogenesis . The disclosed compositions and methods are particularly useful for suppressing the growth and metastasis of tumors.

Cyclic peptide compounds having 11 amino acids joined by a linking unit L, such that the linear dimension between the C carbon of the first amino acid and the C carbon of eleventh amino acid is between about 4 and 12 &angst;ngstrom units; are useful for inhibiting the binding of uPA to the uPAR receptor. Methods for using the cyclic peptide compounds, and compositions containing them, for inhibiting the growth or metastasis of cancerous tumors are also disclosed.

Method of using cyclic peptides to inhibit binding to urokinase-type plasminogen activator receptor

uPAR-targeting cyclic peptide compounds have 11 amino acids that correspond to human uPA(20-30) &lsqb;SEQ ID NO:2&rsqb;, or are substitution variants at selected positions. The N and C terminal residues of these peptides are joined by a linking group L, so that the linear dimension between the a carbons of the first and the eleventh amino acids is between about 4 and 12 &angst;ngstrom units. These cyclic peptides may be further conjugated to diagnostic labels or therapeutic moieties such as radionuclides. Such compounds are usefull for targeting uPAR expressed in pathological tissues and for inhibiting the binding of uPA to the uPAR. The pharmaceutical and therapeutic compositions inhibit cell migration, cell invasion, cell proliferation or angiogenesis, or induce apoptosis, and are thus useful for treating diseases or condition associated with undesired cell migration, invasion, proliferation, or angiogenesis, most notably cancer. The cyclic peptides are also used to detect and isolate cells expressing uPAR.

Cyclic peptide ligands that target urokinase plasminogen activator receptor

Anti-invasive and anti-angiogenic compositions and methods

Cyclic peptide compounds having 11 amino acids joined by a linking unit L, such that the linear dimension between the C.sup..alpha. carbon of the first amino acid and the C.sup..alpha. carbon of eleventh amino acid is between about 4 and 12 .ANG.ngstrom units; are useful for inhibiting the binding of uPA to the uPAR receptor. Methods for using the cyclic peptide compounds, and compositions containing them, for inhibiting the growth or metastasis of cancerous tumors are also disclosed.

Cyclic peptides that bind to urokinase-type plasminogen activator

Quinazoline compounds which demonstrate antiproliferative activity, such as antitumor activity, processes of preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds. These compounds inhibit the growth and proliferation of the cells of higher organisms and microorganisms, such as bacteria, yeasts and fungi. Preferred quinazoline compounds are capable of inhibiting the enzyme thymidylate synthase. Effects derived from the inhibition of the enzyme thymidylate synthase include those discussed above.

Antiproliferative quinazolines

The invention relates to TS-inhibiting compounds of the formula ##STR1## where W is an alkylene group; D is a structure having two rings that are unsubstituted or substituted, where (i) one ring is a phenyl ring and (ii) the other ring is a phenyl ring or a 6-membered heterocyclic ring; R is a hydrogen atom or an alkyl group; and X and Y together form ##STR2## and to salts of these compounds. The moiety W can be CH.sub.2, and D can be a phenyl ring bridged through a sulfonyl group to another ring.

Growing community of inventors

San Diego, CA, United States of America

Terence R Jones