WO1998043629A1 - Anti-inflammatory medicament containing farnesyl protein transferase inhibitor, its preparation and use - Google Patents
Anti-inflammatory medicament containing farnesyl protein transferase inhibitor, its preparation and use Download PDFInfo
- Publication number
- WO1998043629A1 WO1998043629A1 PCT/GB1998/000976 GB9800976W WO9843629A1 WO 1998043629 A1 WO1998043629 A1 WO 1998043629A1 GB 9800976 W GB9800976 W GB 9800976W WO 9843629 A1 WO9843629 A1 WO 9843629A1
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- WIPO (PCT)
- Prior art keywords
- amino
- methionine
- mercaptopropylamino
- valyl
- inhibitor
- Prior art date
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- DGTFNAFXRTYEDI-UHFFFAOYSA-N CCC(C)C(C(NCc1cccc(Cl)c1Cl)=O)NCC(CS)N Chemical compound CCC(C)C(C(NCc1cccc(Cl)c1Cl)=O)NCC(CS)N DGTFNAFXRTYEDI-UHFFFAOYSA-N 0.000 description 1
- LMBPTRXCFXWLRW-XDNKCEHLSA-N C[C@H](C(N)=O)NC([C@H](Cc1c[nH]c2c1cccc2)NC(C(COCc1ccccc1)NC([C@H](Cc(cc1)ccc1OCc1ccccc1)NC(C(Cc1c[nH]cn1)NC(OCc1ccccc1)=O)=O)=O)=O)=O Chemical compound C[C@H](C(N)=O)NC([C@H](Cc1c[nH]c2c1cccc2)NC(C(COCc1ccccc1)NC([C@H](Cc(cc1)ccc1OCc1ccccc1)NC(C(Cc1c[nH]cn1)NC(OCc1ccccc1)=O)=O)=O)=O)=O LMBPTRXCFXWLRW-XDNKCEHLSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- the enzyme farnesyl protein transferase (EC 2 5 1 p21 AS farnesyl transferase, FPTase) is a key component in the post-translational processing of a number of cellular proteins It catalyses the reaction between farnesyl pyrophosphate and proteins which have as their C-terminal sequence a "CaaX" motif (where C is cysteine, a is an aliphatic amino-acid and X is one of a number of amino-acids including se ⁇ ne, methionine and glutamine)
- CaaX is an aliphatic amino-acid
- X is one of a number of amino-acids including se ⁇ ne, methionine and glutamine
- FIGURE 1 CaaX ANALOGUES
- FIGURE 2 FARNESYL PYROPHOSPHATE ANALOGUES
- FIGURE 3 MISCELLANEOUS INHIBITORS
- the invention descnbed herein is a new use for a group of compounds which have been disclosed in the past
- the compounds are characterised in that they are inhibitors of the enzyme farnesyl protein transferase
- the new use of these compounds is as therapeutic agents in the treatment of inflammatory diseases, particularly those involving an immune component
- the invention is accordingly also a method of treatment for these disease conditions
- Such conditions include, but are not limited to ulcerative colitis, Crohn's disease, allergic rhinitis, graft-vs-host disease, conjunctivitis, asthma, rheumatoid arthritis, osteoarth ⁇ tis, ARDS, Behcet's disease, transplant rejection, utica ⁇ a, allergic dermatitis, allopecia areata, scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphyse
- the invention includes the use of medicinal formulations for the treatment of inflammatory diseases in which a compound as described above is used as an active principal.
- Such formulations will have as other ingredients such materials as bulking and binding agents and preservatives as are well known in the art.
- the formulation may be a tablet, solution, suspension, aerosol, cream, suppository or any other form appropriate for the administration of the active principal.
- the administration can be topical, by intravenous, subcutaneous or intramuscular injection, or via the oral, opthalmological, nasal, bucal, rectal or vaginal routes.
- the amount of formulation (and hence the amount of active principal) will be chosen by the treating physician taking into account the age, weight and state of health of the patient as well as any other factors he considers to be relevant.
- the amount of active principal used will generally be between 0. lmg and lOg per day in a single dose or in divided doses. Preferably the amount will be between lmg and lg.
- the efficacy of the compounds can be assessed in a number of assays using either isolated human T lymphocytes or whole animal models of immunoinflammation. Some of these assays are described in the following Examples.
- Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days [ 3 H]thymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction.
- the compounds of the invention inhibit proliferation at concentrations equal to or below 50 ⁇ M. Typical results are shown in the Table in which:
- Compound 1 is more fully identified as l-(2-amino-3-mercaptopropyl)-2-butyl-4-(l- naphthoyl)piperazine, a farnesyl protein transferase inhibitor described by Williams et al. (J.Med.Chem. 1996, 39, 1345)
- Human T-lymphocytes are stimulated to proliferate with interleukin-2 in the presence of varying concentrations of the test compound. After 3 days [ 3 H]thymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction.
- the compounds of the invention inhibit proliferation at concentrations equal to or below 50 ⁇ M. Typical results are shown in the Table in which:
- Compound 1 is more fully identified as l-(2-amino-3-mercaptopropyl)-2-butyl-4-(l- naphthoyl)piperazine, a farnesyl protein transferase inhibitor described by Williams et al. (J.Med.Chem. 1996, 39, 1345)
Abstract
Medicament containing inhibitor of farnesyl protein transferase for the treatment of an inflammatory pathological condition or the associated pain, and the preparation and use thereof.
Description
ANΗ-INFLAMMATORY MEDICAMENT CONTAINING FARNESYL PROTEIN TRANSFERASE INHIBITOR, ITS PREPARATION AND USE
BACKGROUND
The enzyme farnesyl protein transferase (EC 2 5 1 p21 AS farnesyl transferase, FPTase) is a key component in the post-translational processing of a number of cellular proteins It catalyses the reaction between farnesyl pyrophosphate and proteins which have as their C-terminal sequence a "CaaX" motif (where C is cysteine, a is an aliphatic amino-acid and X is one of a number of amino-acids including seπne, methionine and glutamine) The outcome of the reaction is the formation of a thioether in which the farnesyl unit is covalently linked to the cysteine sulphur atom (Scheme 1)
Farnesyl pyrophosphate "CaaX" protein
FPTase
Amongst the most widely investigated families of protein substrates for FPTase are the products of the ras genes, p21ra\ including Kirsten (K-)ras, Harvey (Ha-)ras and N-ras as proteins are GTPases that control a number of intracellular signal transduction cascades In order to function correctly, the ras proteins need to be localised at a cell membrane The presence of a lipophihc farnesyl group at the C-terminus is a key determinant for effective translocation from the cytosol to the membrane, so inhibition of FPTase can result in failure of the protein to localise correctly and hence can lead to blockade of the downstream signals i
A number of groups have found inhibitors of FPTase. The compounds that have been reported are structurally diverse. Many are analogues of the "CaaX" motif, a smaller number are analogues of farnesyl pyrophosphate or of the two substrates together, and a few have no obvious structural relationship to either substrate. Representative examples are illustrated in the figures below.
FIGURE 1: CaaX ANALOGUES
FIGURE 3: MISCELLANEOUS INHIBITORS
The utility of these compounds has been studied particularly in the area of anti-cancer therapy Ras mutations are prevalent in a number of tumours, and they are presumed to have a role in the etiology of the disease in these cases FPTase inhibitors have been tried in animal models of cancer with good results Experimental tumours regress dunng treatment and do not recur until the drug is withdrawn Importantly, no drug toxicity is seen even after prolonged treatment In consequence, it has been suggested that FPTase inhibitors have no effect on "normal" tissue (I e tissue that does not express mutant activated ras)
We have now found evidence that inhibitors of FPTase do have an effect on T lymphocytes which have no ras mutations This unexpected finding suggests a new therapeutic role for FPTase inhibitors in the management of pathophysiological conditions in which there is involvement of T lymphocytes These will typically be diseases which are characteπsed by an immunoinflammatory component, and include, for example, inflammatory bowel disease (ulcerative colitis and Crohn's disease), asthma and rheumatoid arthntis
DETAILED DESCRIPTION OF THE INVENTION
The invention descnbed herein is a new use for a group of compounds which have been disclosed in the past The compounds are characterised in that they are inhibitors of the enzyme farnesyl protein transferase The new use of these compounds is as therapeutic agents in the treatment of inflammatory diseases, particularly those involving an immune component The invention is accordingly also a method of treatment for these disease conditions Such conditions include, but are not limited to ulcerative colitis, Crohn's disease, allergic rhinitis, graft-vs-host disease, conjunctivitis, asthma, rheumatoid arthritis, osteoarthπtis, ARDS, Behcet's disease, transplant rejection, uticaπa, allergic dermatitis, allopecia areata, scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis, chronic bronchitis and psoπasis The compounds can also be used for the treatment of pain associated with inflammatory conditions The invention includes farnesyl protein transferase inhibitors that are analogues of the CaaX motif, analogues of the co-substrate farnesyl pyrophosphate, bisubstrate analogues, and natural and synthetic compounds that have little obvious structural analogy to either substrate In particular it includes (but is not limited to)
N-(2-(3-(N'-Cysteinyl-N'-methylamino)-4-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-l- yl)acetyl)methionine
N-(2-(3-(N' -Cysteinyl-N' -methylamino)-4-phenyl-2 ,3-dihydro- 1 H- 1 ,4-benzodiazepin- 1 - yl)acetyl)methionine methyl ester
N-(4-(2'-Amino-3,-mercaptopropylamino)-2-phenylbenzoyl)methionine
N-(4-(2'-Amino-3'-mercaptopropylamino)-2-phenylbenzoyl)methionine methyl ester
4-(2-Amino-3-mercaptopropylamino)biphenyl-3'-carboxylic acid
(R*)-N-[[l,2,3,4-Tetrahydro-2-[N-(2-(lΗ-imidazol-4-yl)ethyl]-L-valyl]-3- isoquinolinyl]carbonyl]-L-methionine
N-((Farnesylphosphonyloxy)acetyl)valyl-valyl-methionine
N-(3-(Famesylphosphonyl)propionyl)valyl-valyl-methionine
N-(3-(Famesylphosphonyl)propionyl)valyl-valyl-methionine methyl ester
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyl]isoleucyl-homoserine lactone
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyl]isoleucyl-homoserine
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyl]methioninesulphone methyl ester
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyljmethioninesulphone
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyljmethioninesulphone isopropyl ester
1 -(2-Amino-3-mercaptopropyl)-2-(2-methoxyethyl)-4-( 1 -naphthoyl)piperazine
1 -(2-Amino-3-mercaptopropy l)-2-butyl-4-( 1 -naphthoyl)piperazine
N-((lR,2R,4E)-5-(2-Benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)pent-4-enyl)- 3,3-bis(carboxy)-N-(2-naphthylmethyl)glutaramic acid
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3-methylbutyl]phenylalanyl-methionine
N-(8-A_mino-2-benzyl-9-mercapto-5-(2-propyl)non-6-enoyl)methionine
N-(8-Amino-2-benzyl-9-mercapto-5-(2-propyl)non-6-enoyl)methionine methyl ester
The invention includes the use of medicinal formulations for the treatment of inflammatory diseases in which a compound as described above is used as an active principal. Such formulations will have as other ingredients such materials as bulking and binding agents and preservatives as are well known in the art. The formulation may be a tablet, solution, suspension, aerosol, cream, suppository or any other form appropriate for the administration of the active principal. The administration can be topical, by intravenous, subcutaneous or intramuscular injection, or via the oral, opthalmological, nasal, bucal, rectal or vaginal routes.
When used to treat these conditions the amount of formulation (and hence the amount of active principal) will be chosen by the treating physician taking into account the age, weight and state of health of the patient as well as any other factors he considers to be relevant. The amount of active principal used will generally be between 0. lmg and lOg per day in a single dose or in divided doses. Preferably the amount will be between lmg and lg.
The efficacy of the compounds can be assessed in a number of assays using either isolated human T lymphocytes or whole animal models of immunoinflammation. Some of these assays are described in the following Examples.
EXAMPLE 1
Proliferation of T lymphocytes driven by CD3
Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days [3H]thymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction. The compounds of the invention inhibit proliferation at concentrations equal to or below 50μM. Typical results are shown in the Table in which:
Compound 1 is more fully identified as l-(2-amino-3-mercaptopropyl)-2-butyl-4-(l- naphthoyl)piperazine, a farnesyl protein transferase inhibitor described by Williams et al. (J.Med.Chem. 1996, 39, 1345)
Concentration (μM) Inhibition (%)
Compound 1 41
EXAMPLE 2
Proliferation of T lymphocytes driven by IL-2
Human T-lymphocytes are stimulated to proliferate with interleukin-2 in the presence of varying concentrations of the test compound. After 3 days [3H]thymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction. The compounds of the invention inhibit proliferation at concentrations equal to or below 50μM. Typical results are shown in the Table in which:
Compound 1 is more fully identified as l-(2-amino-3-mercaptopropyl)-2-butyl-4-(l- naphthoyl)piperazine, a farnesyl protein transferase inhibitor described by Williams et al. (J.Med.Chem. 1996, 39, 1345)
Concentration (μM) Inhibition (%)
Compound 72
Claims
1. The use, for the preparation of a medicament for the treatment of an inflammatory pathological condition or the associated pain, of inhibitor of farnesyl protein transferase.
2. The use of claim 1 in which the inflammatory condition has an immunological component.
3. The use of claim 1 or 2 in which the inflammatory condition is ulcerative colitis, Crohn's disease, allergic rhinids, graft-vs-hosc disease, conjunctivitis, asthma, rheumacoid arthritis, osteoarthiitis, ARDS, Behcet's disease, transplant rejection, uticaria, allergic dermatitis, allopecia areata, sclerodeπna, exand em, eczema, dermatomyositis, acne, diabeces, syscemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis, chronic bronchitis or psoriasis.
4. The use of any preceding claim in which the inhibitor of farnesyl protein transferase is selected from :
N-(2-(3-(N'-Cysteinyl-N'-methylamino)-4-phenyl-2)3-dihydro- lH-l ,4-benzodiazepin-l- yl)acetyl)methionine
N-(2-(3-(N'-Cysteinyl-N'-methylamino)-4-phenyl-2,3-dihydro-lH-l ,4-benzodiazepin-l- yl)acetyl)methionine methyl ester
N-(4-(2'-Amino-3'-mercaptopropylamino)-2-phenylbenzoyl)methionine, N-(4-(2'-Amino-3'-mercaptopropylamino)-2-phenylbenzoyl)methionine methyl estery
4-(2-Amino-3-mercaptopropylamino)biphenyl-3'-carboxylic acid,
(R*)-N-[[l,2)3,4-Tetrahydro-2-[N-(2-(lH-imidazol-4-yl)ethyl]-L-valyl]-3- isoquinolinyl]carbonyl]-L-methionine
N-((Farnesylphosphonyloxy)acetyl)valyl-valyl-methionine/
N-(3-(Famesylphosphonyl)propionyl)valyl-valyl-methionineJ
N-(3-(Famesylphosphonyl)propionyl)valyl-valyl-methionine methyl ester,
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyl]isoleucyl-homoserine lactone ,
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyl]isoleucyl-homoserine,
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyljmethioninesulphone methyl ester
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyl]methioninesulphone
N-[2(S)-(2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3- phenylpropionyl]methioninesulphone isopropyl ester
l-(2-Amino-3-mercaptopropyl)-2-(2-methoxyethyl)-4-(l-naphthoyl)piperazine l-(2-Amino-3-mercaptopropyl)-2-butyl-4-(l-naphthoyl)piperazine,
N-((lR,2R,4E)-5-(2-Benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)pent-4-enyl)- 3,3-bis(carboxy)-N-(2-naphthylmethyl)glutaramic acid,
N-[2(SH2(R)-Amino-3-mercaptopropylamino)-3-methylbutyl]phenylalanyl-methionine.
N-(8-Amino-2-benzyl-9-mercapto-5-(2-propyl)non-6-enoyl)methionine^ and
N-(8-Amino-2-benzyl-9-mercapto-5-(2-propyl)non-6-enoyl)methionine methyl ester .
5. A pharmaceutical composition containing inhibitor of farnesyl protein transferase for the prevention or treatment of an inflammatory pathological condition or the associated pain.
6. A composition according to claim 5 wherein the condition is as set out in claim 1 or claim 2.
7. A composition according to claim 5 or 6 wherein the inhibitor is selected from those listed in claim 4.
8. A method for the prevention or treatment of an inflammatory pathological condition or the associated pain which comprises administering to the patient inhibitor of farnesyl protein transferase.
9. A method according to claim 8 wherein the condition is as set out in claim 1 or claim 2.
10. A method according to claim 9 or 10 wherein the inhibitor is selected from those listed in claim 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU68474/98A AU6847498A (en) | 1997-04-02 | 1998-04-02 | Anti-inflammatory medicament containing farnesyl protein transferase inhibitor, its preparation and use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9706652A GB2323783A (en) | 1997-04-02 | 1997-04-02 | Inhibitors of farnesyl protein transferase |
| GB9706652.6 | 1997-04-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998043629A1 true WO1998043629A1 (en) | 1998-10-08 |
Family
ID=10810139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1998/000976 WO1998043629A1 (en) | 1997-04-02 | 1998-04-02 | Anti-inflammatory medicament containing farnesyl protein transferase inhibitor, its preparation and use |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6847498A (en) |
| GB (1) | GB2323783A (en) |
| WO (1) | WO1998043629A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000001386A1 (en) * | 1998-07-06 | 2000-01-13 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibitors for treating arthropathies |
| WO2002043733A1 (en) * | 2000-11-28 | 2002-06-06 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibitors for the treatment of inflammatory bowel disease |
| EP2362218A2 (en) | 2004-11-05 | 2011-08-31 | Janssen Pharmaceutica N.V. | Methods of monitoring the efficacy of farnesyltransferase inhibitors |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6071955A (en) * | 1999-02-25 | 2000-06-06 | The Regents Of The University Of California | FXR, PPARA and LXRA activators to treat acne/acneiform conditions |
| GB0023915D0 (en) * | 2000-09-29 | 2000-11-15 | Inst Of Ophthalmology | Treatment of neuroinflammatory disease |
| RS52927B (en) | 2004-12-24 | 2014-02-28 | Spinifex Pharmaceuticals Pty Ltd | Method of treatment or prophylaxis |
| CA2866540A1 (en) * | 2006-03-20 | 2007-09-27 | Spinifex Pharmaceuticals Pty Ltd. | Method of treatment or prophylaxis of inflammatory pain |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0535730A2 (en) * | 1991-09-30 | 1993-04-07 | Merck & Co. Inc. | Inhibitors of farnesyl protein transferase |
| WO1995000497A1 (en) * | 1993-06-18 | 1995-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| GB2294462A (en) * | 1994-10-26 | 1996-05-01 | Merck & Co Inc | Diterpenoid derivatives as inhibitors of prenyl-protein transferases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5089496A (en) * | 1986-10-31 | 1992-02-18 | Schering Corporation | Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies |
-
1997
- 1997-04-02 GB GB9706652A patent/GB2323783A/en not_active Withdrawn
-
1998
- 1998-04-02 AU AU68474/98A patent/AU6847498A/en not_active Abandoned
- 1998-04-02 WO PCT/GB1998/000976 patent/WO1998043629A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0535730A2 (en) * | 1991-09-30 | 1993-04-07 | Merck & Co. Inc. | Inhibitors of farnesyl protein transferase |
| WO1995000497A1 (en) * | 1993-06-18 | 1995-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| GB2294462A (en) * | 1994-10-26 | 1996-05-01 | Merck & Co Inc | Diterpenoid derivatives as inhibitors of prenyl-protein transferases |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000001386A1 (en) * | 1998-07-06 | 2000-01-13 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibitors for treating arthropathies |
| US6451812B1 (en) | 1998-07-06 | 2002-09-17 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibitors for treating arthropathies |
| WO2002043733A1 (en) * | 2000-11-28 | 2002-06-06 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibitors for the treatment of inflammatory bowel disease |
| EP2362218A2 (en) | 2004-11-05 | 2011-08-31 | Janssen Pharmaceutica N.V. | Methods of monitoring the efficacy of farnesyltransferase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2323783A (en) | 1998-10-07 |
| AU6847498A (en) | 1998-10-22 |
| GB9706652D0 (en) | 1997-05-21 |
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