CA2076652A1 - Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase - Google Patents

Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase

Info

Publication number
CA2076652A1
CA2076652A1 CA002076652A CA2076652A CA2076652A1 CA 2076652 A1 CA2076652 A1 CA 2076652A1 CA 002076652 A CA002076652 A CA 002076652A CA 2076652 A CA2076652 A CA 2076652A CA 2076652 A1 CA2076652 A1 CA 2076652A1
Authority
CA
Canada
Prior art keywords
enzyme
disclosed
inhibition
identification
methods
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002076652A
Other languages
French (fr)
Other versions
CA2076652C (en
Inventor
Michael S. Brown
Joseph L. Goldstein
Yuval Reiss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
Original Assignee
Michael S. Brown
Joseph L. Goldstein
Yuval Reiss
Board Of Regents, The University Of Texas System
The Board Of Regents Of The University Of Texas
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27056998&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2076652(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Michael S. Brown, Joseph L. Goldstein, Yuval Reiss, Board Of Regents, The University Of Texas System, The Board Of Regents Of The University Of Texas filed Critical Michael S. Brown
Publication of CA2076652A1 publication Critical patent/CA2076652A1/en
Application granted granted Critical
Publication of CA2076652C publication Critical patent/CA2076652C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1085—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/814—Enzyme separation or purification
    • Y10S435/815—Enzyme separation or purification by sorption

Abstract

Disclosed are methods and compositions for the identification, characterization and inhibition of farnesyl protein transfer-ases, enzymes involved in the farnesylation of various cellular proteins, including cancer related ras proteins such as p21ras. One farnesyl protein transferase which is disclosed herein exhibits a molecular weight of between about 70,000 and about 100,000 up-on gel exclusion chromatography. The enzyme appears to comprise one or two subunits of approximately 50 kDa each. Methods are disclosed for assay and purification of the enzyme, as well as procedures for using the purified enzyme in screening protocols for the identification of possible anticancer agents which inhibit the enzyme and thereby prevent expression of proteins such as p21ras. Also disclosed is a family of compounds which act either as false substrates for the enzyme or as pure inhibitors and can therefore be employed for inhibition of the enzyme. The most potent inhibitors are ones in which phenylalanine occurs at the third position of a tetrapeptide whose amino terminus is cysteine.
CA002076652A 1990-04-18 1991-04-18 Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase Expired - Lifetime CA2076652C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US51070690A 1990-04-18 1990-04-18
US510,706 1990-04-18
US07/615,715 US5141851A (en) 1990-04-18 1990-11-20 Isolated farnesyl protein transferase enzyme
US615,715 1990-11-20
PCT/US1991/002650 WO1991016340A1 (en) 1990-04-18 1991-04-18 Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase

Publications (2)

Publication Number Publication Date
CA2076652A1 true CA2076652A1 (en) 1991-10-19
CA2076652C CA2076652C (en) 2003-06-10

Family

ID=27056998

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002076652A Expired - Lifetime CA2076652C (en) 1990-04-18 1991-04-18 Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase

Country Status (8)

Country Link
US (1) US5141851A (en)
EP (1) EP0528820B2 (en)
JP (1) JPH05506779A (en)
AT (1) ATE143973T1 (en)
AU (1) AU637497B2 (en)
CA (1) CA2076652C (en)
DE (2) DE69122611T3 (en)
WO (1) WO1991016340A1 (en)

Families Citing this family (126)

* Cited by examiner, † Cited by third party
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US6632626B1 (en) * 1990-04-18 2003-10-14 Board Of Regents, The University Of Texas System Methods of assaying farnesyl transferase
US8003342B1 (en) 1990-04-18 2011-08-23 Board Of Regents, The University Of Texas System Method for identifying farnesyl transferase inhibitors
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EP0528820B2 (en) 2001-12-19
CA2076652C (en) 2003-06-10
EP0528820A1 (en) 1993-03-03
ATE143973T1 (en) 1996-10-15
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DE69122611T2 (en) 1997-05-07
WO1991016340A1 (en) 1991-10-31

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