# US 2010/0168019 A1 · Peptide conjugated anti-cancer prodrugs > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2010/0168019 A1 - Document ID: US20100168019A1 - Status: Published application - Kind: A1 - Application number: 12/623,859 - Filed: 2009-11-23 - Published: 2010-07-01 - Earliest claimed: 2000-09-05 - Assignees: Biosight Ltd. - Inventors: Stela Gengrinovitch - Web page: https://patentgrep.com/patent/US20100168019A1 ## CPC - A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to prodrug molecules comprising conjugates of an antiproliferative drug, a protease specific cleavable peptide, and, optionally, a targeting peptide, with the prodrugs being substantially inactive prior to degradation of the cleavable sequence by proteolytic enzymes abundant within or in close proximity to the target cancer cell. Also, pharmaceutical compositions of the conjugates and the use of these compositions for treatment of cancer are disclosed. ## Claims ### Claim 1 A prodrug comprising a conjugate of at least one antiproliferative drug molecule covalently coupled directly or via a linker to a peptide moiety, said peptide moiety being specifically cleavable by an asparaginyl protease abundant in or secreted by malignant cells, thereby preferentially releasing the antiproliferative drug molecule within or at the malignant cells by the cleaving action of the asparaginyl protease. ### Claim 2 (depends on 1) The prodrug of claim 1, wherein the antiproliferative drug is selected from the group consisting of a cytotoxic, a cytostatic or a chemotherapeutic drug. ### Claim 3 (depends on 1) The prodrug of claim 1, wherein the conjugate is substantially pharmacologically inactive. ### Claim 4 (depends on 1) The prodrug of claim 1, wherein the antiproliferative drug is selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, vinca alkaloids, epipodophyllotoxins, nitrosoureas, hormonal and antihormonal agents, and toxins. ### Claim 5 (depends on 1) The prodrug of claim 1, wherein the antiproliferative drug is selected from the group consisting of: cyclophosphamide, chlorambucil, busulfan, Melphalan, Thiotepa, ifosphamide, Nitrogen mustard, methotrexate, 5-Fluorouracil, cytosine arabinoside, 6-thioguanine, 6-mercaptopurine, doxorubicin, daunorubicin, idorubicin, nimitoxantron, dactinomycin, bleomycin, mitomycin, plicamycin, epipodophyllotoxins vincristin, vinblastin, vindestin, Etoposide, Teniposide, carmustin, lomustin, semustin, streptozocin, adrenocorticorticoids, estrogens, antiestrogens, progestins, aromatase inhibitors, androgens, antiandrogens, dacarbazin, hexamethylmelamine, hydroxyurea, mitotane, procarbazide, cisplastin, and carboplatin. ### Claim 6 (depends on 5) The prodrug of claim 5, wherein the antiproliferative drug is selected from a group consisting of Melphalan, Methotrexate, Chlorambucil, Doxorubicin, and 5-fluorouracil. ### Claim 7 (depends on 1) The prodrug of claim 1, wherein the peptide cleavable by the asparaginyl protease consists of from two to about fourteen amino acids at least one of which is asparagine. ### Claim 8 (depends on 1) The prodrug of claim 1, wherein the asparaginyl protease is legumain. ### Claim 9 (depends on 8) The prodrug of claim 8, wherein the peptide cleavable by legumain consists of two to about fourteen amino acids comprising the amino acid sequence X1-X2-X3, wherein X1 is selected from the group consisting of Pro, Thr, Asn, and Ala, X2 is selected from the group consisting of Thr, Pro, Asn, and Ala, and X3 is Asn. ### Claim 10 (depends on 9) The prodrug of claim 9, wherein the peptide cleavable by legumain is selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:32. ### Claim 11 (depends on 1) The prodrug of claim 1 further comprising at least one protecting group capable of preventing digestion of the peptide moiety by nonspecific proteases. ### Claim 12 (depends on 1) The prodrug of claim 1 comprising a plurality of antiproliferative drug molecules. ### Claim 13 (depends on 1) The prodrug of claim 1, wherein the linker between the drug and the peptide comprises any chemical compound which may be removed chemically, enzymatically or which decomposes spontaneously. ### Claim 14 (depends on 8) The prodrug of claim 8, wherein the peptide cleavable by legumain consists of the amino acid sequence selected from the group consisting of SEQ ID NO:33 to SEQ ID NO:38 inclusive. ### Claim 15 (depends on 1) A pharmaceutical composition comprising as an active ingredient a prodrug according to claim 1 together with a pharmaceutically acceptable excipient or diluent. ### Claim 16 (depends on 15) A method of treating a subject suffering from a cancer malignancy comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 15. ### Claim 17 (depends on 16) The method of claim 16, wherein the pharmaceutical composition is administered intravenously. ### Claim 18 (depends on 1) A method for producing a prodrug, the method comprising the step of linking at least one antiproliferative drug molecule and a peptide moiety to form the prodrug of claim 1, with the peptide moiety being specifically cleavable by an asparaginyl protease abundant in or secreted by malignant cells. ### Claim 19 (depends on 18) The method of claim 18, wherein the antiproliferative drug is selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, vinca alkaloids, epipodophyllotoxins, nitrosoureas, hormonal and antihormonal agents, and toxins. ### Claim 20 (depends on 18) The method of claim 18, wherein the peptide moiety cleavable by the asparaginyl protease consists from two to about fourteen amino acids at least one of which is asparagine. ### Claim 21 (depends on 18) The method of claim 18, wherein the asparaginyl protease is legumain.