Title:
METHODS AND COMPOSITIONS FOR RESTORING CONFORMATIONAL STABILITY OF A PROTEIN OF THE p53 FAMILY
Document Type and Number:
WIPO Patent Application WO2000032175
Kind Code:
A3
Abstract:
The invention provides pharmaceutical non-peptidic organic compounds capable of interacting with a functionally defective form of a mutant or a wild-type tumor suppressor protein of the p53 family (such as p53, p63 or p73). The interaction allows stabilization or folding of the protein in a functional conformation, thereby restoring all or part of its wild-type normal activity. More particularly said compounds interact with the DNA binding domain of p53 family proteins, are acridine, quinoline, quinazoline or phenothiazine derivatives, and are used in cancer therapy. Also provided are methods for screening such pharmacological compounds.
Inventors:
COFFEY HEATHER ANNE
CONNELL RICHARD DAMIAN
FOSTER BARBARA ANN
RASTINEJAD FARZAN
CONNELL RICHARD DAMIAN
FOSTER BARBARA ANN
RASTINEJAD FARZAN
Application Number:
PCT/IB1999/001916
Publication Date:
August 03, 2000
Filing Date:
December 01, 1999
Export Citation:
Assignee:
PFIZER PROD INC (US)
International Classes:
A61K31/00; A61K31/47; A61K31/473; A61K31/517; A61K31/5415; A61K45/08; C12N15/09; A61P3/06; A61P7/04; A61P21/04; A61P25/00; A61P25/28; A61P27/02; A61P27/12; A61P35/00; A61P43/00; C07D219/12; C07D221/08; C07D221/18; C07D239/94; C07D279/26; C07D417/12; C07K14/47; (IPC1-7): A61K31/5415; A61K31/473; A61K31/496; A61K31/517; A61P35/00; G01N33/50
Domestic Patent References:
| WO1994012202A1 | 1994-06-09 | |||
| WO1997037645A1 | 1997-10-16 |
Other References:
HAINAUT ET AL.: "Redox modulation of p53 conformation and sequence DNA-binding in-vitro", CANCER RESEARCH, vol. 35, no. 18, 1 October 1993 (1993-10-01), pages 4469 - 4473, XP000891856
RYAN ET AL.: "Alteration of p53 conformation and induction of apoptosis in a murine erythroleukemia cell line by dimethylsulfoxide", LEUKEMIA RESEARCH, vol. 18, no. 8, 1994, pages 617 - 621, XP000901852
BROWN ET AL.: "Chemical chaperones correct the temperature sensitive protein folding defects associated with p53 and ubiquitin", MOL. BIOL. CELL., vol. 7, no. suppl., December 1996 (1996-12-01), pages 337a, XP000901864
BROWN ET AL.: "Correcting temperature-sensitive protein folding defects", J. CLIN. INVEST., vol. 99, no. 6, 15 March 1997 (1997-03-15), pages 1432 - 1444, XP000901689
SHEKHAR ET AL.: "Altered p53 conformation: a novel mechanism of wild-type p53 functional inactivation in a model for early breast cancer", INT. J. ONCOL., vol. 11, no. 5, November 1997 (1997-11-01), pages 1087 - 1094, XP000901870
HAINAUT ET AL.: "A structural role for metal ions in the "wild-type" conformation of the tumor suppressor protein p53", CANCER RESEARCH, vol. 53, no. 8, 1993, pages 1739 - 1742, XP000891855
BLAGOSKLONNY ET AL.: "Geldanamycin selectively destabilizes mutant p53", PROC. ANNU. MEET. AM. ASSOC. CANCER RES., vol. 36, March 1995 (1995-03-01), pages 429, XP000891847
CHEMICAL ABSTRACTS, vol. 124, no. 25, 17 June 1996, Columbus, Ohio, US; abstract no. 332043, SAKAGAMI, KIROSHI ET AL: "Induction of DNA fragmentation in human myelogenous leukemic cell lines by phenothiazine-related compounds" XP000901771
CHEMICAL ABSTRACTS, vol. 128, no. 14, 6 April 1998, Columbus, Ohio, US; abstract no. 162631, WUONOLA, MARK A. ET AL: "The primary in vitro antitumor screening of "half-mustard type" phenothiazines" XP000901768
NAGY ET AL.: "Antitumor activity of phenothiazine-related compounds", CANCER RESEARCH, vol. 16, no. 4a, 1996, pages 1915 - 1918, XP000901776
MOTOHASHI ET AL.: "Synthesis and antitumor activity of 1-[2-(chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)ALKYL-1] ureas as potent anticancer agents", ANTICANCER RESEARCH, vol. 16, no. 5a, 1996, pages 2525 - 2532, XP000901777
GNIAZDOWSKI ET AL.: "Thiol-dependent inhibition of RNA synthesis in-vitro by acridines,. Structure-inhibition relationship", CANCER LETTERS, vol. 15, no. 1, 1982, pages 73 - 79, XP000901862
WILSON ET AL.: "Hypoxia-selective antituomr agents. 2. Electronic effects of 4-substituents on the mechanisms of cytotoxicity and metabolic stability of nitracrine derivatives", J. MED. CHEM., vol. 32, no. 1, 1989, pages 31 - 38, XP000891841
HUPP ET AL.: "Regulation of p53 protein function through alterations in protein-folding pathways", CELL. MOL. LIFE SCI., vol. 55, no. 1, January 1999 (1999-01-01), pages 88 - 95, XP000891820
OHNISHI ET AL.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone", RADIATION RES., vol. 151, no. 4, April 1999 (1999-04-01), pages 498 - 500, XP000904809
RYAN ET AL.: "Alteration of p53 conformation and induction of apoptosis in a murine erythroleukemia cell line by dimethylsulfoxide", LEUKEMIA RESEARCH, vol. 18, no. 8, 1994, pages 617 - 621, XP000901852
BROWN ET AL.: "Chemical chaperones correct the temperature sensitive protein folding defects associated with p53 and ubiquitin", MOL. BIOL. CELL., vol. 7, no. suppl., December 1996 (1996-12-01), pages 337a, XP000901864
BROWN ET AL.: "Correcting temperature-sensitive protein folding defects", J. CLIN. INVEST., vol. 99, no. 6, 15 March 1997 (1997-03-15), pages 1432 - 1444, XP000901689
SHEKHAR ET AL.: "Altered p53 conformation: a novel mechanism of wild-type p53 functional inactivation in a model for early breast cancer", INT. J. ONCOL., vol. 11, no. 5, November 1997 (1997-11-01), pages 1087 - 1094, XP000901870
HAINAUT ET AL.: "A structural role for metal ions in the "wild-type" conformation of the tumor suppressor protein p53", CANCER RESEARCH, vol. 53, no. 8, 1993, pages 1739 - 1742, XP000891855
BLAGOSKLONNY ET AL.: "Geldanamycin selectively destabilizes mutant p53", PROC. ANNU. MEET. AM. ASSOC. CANCER RES., vol. 36, March 1995 (1995-03-01), pages 429, XP000891847
CHEMICAL ABSTRACTS, vol. 124, no. 25, 17 June 1996, Columbus, Ohio, US; abstract no. 332043, SAKAGAMI, KIROSHI ET AL: "Induction of DNA fragmentation in human myelogenous leukemic cell lines by phenothiazine-related compounds" XP000901771
CHEMICAL ABSTRACTS, vol. 128, no. 14, 6 April 1998, Columbus, Ohio, US; abstract no. 162631, WUONOLA, MARK A. ET AL: "The primary in vitro antitumor screening of "half-mustard type" phenothiazines" XP000901768
NAGY ET AL.: "Antitumor activity of phenothiazine-related compounds", CANCER RESEARCH, vol. 16, no. 4a, 1996, pages 1915 - 1918, XP000901776
MOTOHASHI ET AL.: "Synthesis and antitumor activity of 1-[2-(chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)ALKYL-1] ureas as potent anticancer agents", ANTICANCER RESEARCH, vol. 16, no. 5a, 1996, pages 2525 - 2532, XP000901777
GNIAZDOWSKI ET AL.: "Thiol-dependent inhibition of RNA synthesis in-vitro by acridines,. Structure-inhibition relationship", CANCER LETTERS, vol. 15, no. 1, 1982, pages 73 - 79, XP000901862
WILSON ET AL.: "Hypoxia-selective antituomr agents. 2. Electronic effects of 4-substituents on the mechanisms of cytotoxicity and metabolic stability of nitracrine derivatives", J. MED. CHEM., vol. 32, no. 1, 1989, pages 31 - 38, XP000891841
HUPP ET AL.: "Regulation of p53 protein function through alterations in protein-folding pathways", CELL. MOL. LIFE SCI., vol. 55, no. 1, January 1999 (1999-01-01), pages 88 - 95, XP000891820
OHNISHI ET AL.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone", RADIATION RES., vol. 151, no. 4, April 1999 (1999-04-01), pages 498 - 500, XP000904809
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