EP1007076A1 - Procede permettant d'antagoniser le domaine humain src sh2 - Google Patents

Procede permettant d'antagoniser le domaine humain src sh2

Info

Publication number
EP1007076A1
EP1007076A1 EP98910294A EP98910294A EP1007076A1 EP 1007076 A1 EP1007076 A1 EP 1007076A1 EP 98910294 A EP98910294 A EP 98910294A EP 98910294 A EP98910294 A EP 98910294A EP 1007076 A1 EP1007076 A1 EP 1007076A1
Authority
EP
European Patent Office
Prior art keywords
domain
glu
src
peptidomimetic
compound
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.)
Withdrawn
Application number
EP98910294A
Other languages
German (de)
English (en)
Other versions
EP1007076A4 (fr
Inventor
Dennis A. Holt
Daniel F. Veber
Dennis S. Yamashita
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1007076A1 publication Critical patent/EP1007076A1/fr
Publication of EP1007076A4 publication Critical patent/EP1007076A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • An activated osteoclast resorbs bone by attaching to the bone matrix, and secreting proteolytic enzymes, organic acids and protons into the sealed compartment formed between its cell membrane and the bone matrix.
  • the acidic environment and proteolytic enzymes effect the dissolution of bone in the sealed compartment to crest pits, or lacuna, in the bone surface, which are apparent when the osteoclast detaches from the bone.
  • antagonism of the src SH2 domain is indicated herein as effecting bone resorption while antagonism of the lck SH2 domain or the fyn SH2 domain induces immunosuppression.
  • the induction of immunosuppression would be undesirable in long term therapy for bone resorption disease.
  • a bone resorption disease means any disorder characterized by abnormal bone loss due to osteoclastic activity, preferably osteoporosis.
  • the invention also provides a method of treating osteoporosis in a subject which comprises administering to the subject a therapeutically effective amount of a compound which forms a covalent bond or link to cys 185 of the src SH2 domain.
  • the invention also provides a method of impairing the function of osteoclasts in a subject which comprises administering to the subject an osteoclast function-inhibiting amount of a compound which forms a covalent bond or link to cys 185 of the src SH2 domain.
  • the nonreceptor tyrosine kinase src is essential for resorption of bone by osteoclasts.
  • the src homology-2 (SH2) domain of src controls its association with other signaling molecules through binding to short peptide motifs containing phosphotyrosine. Inhibition of these interactions blocks src-mediated signal transduction by preventing recruitment of src into receptor-effector complexes.
  • cysteine 185 (cys 185) is located in the phosphotyrosine binding pocket, close to histidine 201, argl55, argl75 and lys203.
  • Compounds which form a covalent bond or link to cys 185 block the phosphotyrosine binding pocket of human src SH2 thereby irreversibly inhibiting human src SH2.
  • the compound which forms a covalent bond or link to cys 185 will also form a hydrogen bond with arg 175 and have a hydrophobic interaction with the sidechain portion of lys203.
  • the method of treating a bone resorption disease disclosed in the present invention may also be carried out using a pharmaceutical composition comprising an src SH2 domain antagonists defined herein and a pharmaceutically acceptable carrier.
  • the composition may contain between 0.05 mg and 500 mg of a src SH2 domain antagonist, and may be constituted into any form suitable for the mode of administration selected.
  • Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixers, and suspensions.
  • Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • the invention also provides for the use of a src SH2 domain antagonists in the manufacture of a medicament for use in the treatment of a bone resorption disease.
  • the invention also provides for the use of a src SH2 domain antagonists in the manufacture of a medicament for use in inhibiting osteoclast function.
  • N-Acetyl-3-(l,3-dithiane)-4-(t-butyl-carboxylate)-phenylalanine-glutamate- glutamate-isoleucine-glutamate-amine 5mg, 0.006 mmol was dissolved in 90 % acetone/ H 2 O (0.3 ml), then N-chlorosuccinimide (5 mg, 0.037 mmol) and silver perchlorate (10 mg, 0.048 mmol) were added and the reaction was stirred 10 minutes at RT.
  • the reaction mixture was chromatographed (C 18 reverse phase silica, MeCN, H 2 O), and the UV active fractions were combined, concentrated in vacuo, and dissolved in MeOH (0.2 ml).
  • the chicken src SH2 domain was expressed as DET1-DET2- spacer-SH2. Then, the other was inserted into this vector in place of chicken src to express protein in the form DETl-DET2-spacer-ek-spacer-SH2.
  • the PCR product was digested with BamHI and Xbal, followed by isolation of the digested fragment on an agarose gel.
  • the fragment was ligated into BamHI- Xbal-digested expression vector containing the tagged chicken src gene DET1- DET2-spacer-SH2 described in Procedure 1 above.
  • the BamHI site is located between the coding regions for DET2 and SH2, and the Xbal site is located after the 3' end of the SH2 coding region.
  • the ligation reaction was used to transform E. coli MM294cI + .
  • the construct DETl-DET2-spacer-ek-src SH2 was confirmed by DNA sequencing (SEQ ID NO: 5) and induced in E. coli strain AR120 as described in Procedure 1 above.
  • a Coomassie-Blue-stained, Western- blot-positive induced protein band with an apparent molecular weight of 16,000 was observed after nalidixic acid induction.
  • Binding Assays The potency of compounds at the human SH2 domain was determined based on the ability of such compound to selectively inhibit the SH2 domain from binding to its respective specific pY peptide.
  • Tables I and II illustrate the activity of SH2 antagonists at the human src SH2 domain.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une méthode de traitement d'une maladie de résorption osseuse chez un patient, cette méthode consistant à administrer au sujet une dose thérapeutique efficace d'un composé qui forme une fixation ou une liaison covalente avec cys 185 du domaine src SH2. Les composés préférés pour une utilisation dans ladite méthode sont les composés de l'invention qui sont représentés par la formule (I) ou bien leur sel, hydrate ou solvate pharmaceutiquement acceptables. Dans la formule, X représente OR'', SR'', NR'', R'''; R'' représente H, méthyle, alkyle; R''' représente CONH2, CONHMe, CO NHalkyle, SONH2, SONHMe, SONH alkyle, SO2NH2, SO2NHMe, SO2NH alkyle; n représente 0,1 ou 2; R représente H, CH2CH(NHCOR'''')CONHR'''''; une fraction organique; R'''' représente glu-glu-ileu-glu-NH2, peptide, peptidomimétique, alkyle, alkyle substitué, aryle, aryle substitué, hétéroaryle, hétéroaryle substitué; R' représente H, peptidomimétique; ou R, R' représentent un système d'anneau fusionné substitué par H ou peptidomimétique. Cette invention concerne également une composition pharmaceutique contenant un excipient pharmaceutique approprié et un composé de formule (I).
EP98910294A 1997-03-10 1998-03-10 Procede permettant d'antagoniser le domaine humain src sh2 Withdrawn EP1007076A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4065897P 1997-03-10 1997-03-10
US40658P 1997-03-10
PCT/US1998/004699 WO1998040093A1 (fr) 1997-03-10 1998-03-10 Procede permettant d'antagoniser le domaine humain src sh2

Publications (2)

Publication Number Publication Date
EP1007076A1 true EP1007076A1 (fr) 2000-06-14
EP1007076A4 EP1007076A4 (fr) 2004-10-27

Family

ID=21912217

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98910294A Withdrawn EP1007076A4 (fr) 1997-03-10 1998-03-10 Procede permettant d'antagoniser le domaine humain src sh2

Country Status (4)

Country Link
EP (1) EP1007076A4 (fr)
JP (1) JP2001514662A (fr)
CA (1) CA2283472A1 (fr)
WO (1) WO1998040093A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1030853A1 (fr) 1997-11-12 2000-08-30 Ariad Pharmaceuticals, Inc. Nouveaux inhibiteurs de transduction de signal, compositions les contenant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025118A2 (fr) * 1994-03-15 1995-09-21 Trustees Of Tufts University Inhibiteurs d'interactions des domaines sh2
EP0727211A1 (fr) * 1995-02-10 1996-08-21 Smithkline Beecham Corporation Emploi de composés spécifiques src SH2 dans le traitement de maladies de résorption osseuse

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025118A2 (fr) * 1994-03-15 1995-09-21 Trustees Of Tufts University Inhibiteurs d'interactions des domaines sh2
EP0727211A1 (fr) * 1995-02-10 1996-08-21 Smithkline Beecham Corporation Emploi de composés spécifiques src SH2 dans le traitement de maladies de résorption osseuse

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DUNNINGTON E.A.: "Inhibition of bone resorption by src SH2 domain antagonists" J.BONE.MIN.RES., vol. 11, 1996, page S398, XP008034025 *
See also references of WO9840093A1 *

Also Published As

Publication number Publication date
WO1998040093A1 (fr) 1998-09-17
EP1007076A4 (fr) 2004-10-27
CA2283472A1 (fr) 1998-09-17
JP2001514662A (ja) 2001-09-11

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