Small molecule compositions for binding to hsp90

Details Small molecule compositions for binding to hsp90 Small molecule compositions for binding to hsp90

2001-11-01

2008-10-21

Berch, Mark L (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S264000, C544S265000, C544S276000

Reexamination Certificate

active

07439359

ABSTRACT:
Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

REFERENCES:
patent: 2729642 (1956-01-01), Burgison
patent: 3930005 (1975-12-01), Wojnar et al.
patent: 4172829 (1979-10-01), Naito et al.
patent: 5110818 (1992-05-01), Allgeier
patent: 5387584 (1995-02-01), Schnur
patent: 5565566 (1996-10-01), Olsson
patent: 5714494 (1998-02-01), Connell et al.
patent: 5736549 (1998-04-01), Beasley et al.
patent: 5932566 (1999-08-01), Schnur et al.
patent: 6210974 (2001-04-01), Gold
patent: 6294541 (2001-09-01), Cavalla et al.
patent: 6335157 (2002-01-01), Gonzalez et al.
patent: 6413975 (2002-07-01), Chasin et al.
patent: 6440982 (2002-08-01), Maw et al.
patent: 6946456 (2005-09-01), Rosen et al.
patent: 2005/0049263 (2005-03-01), Kasibhatla et al.
patent: 2005/0113340 (2005-05-01), Kasibhatla et al.
patent: 2007/0129334 (2007-06-01), Kasibhatla et al.
patent: 193454 (1986-09-01), None
patent: WO 96/32480 (1996-10-01), None
patent: WO 96/40789 (1996-12-01), None
patent: WO 97/04801 (1997-02-01), None
patent: WO 98/51702 (1998-11-01), None
patent: WO 00/59449 (2000-10-01), None
patent: WO 00/61578 (2000-10-01), None
Obermann, J Cell Biol. Nov. 16, 1998;143(4):901-10.
Panouse, Annales Pharma. Francaises 58(5) 291-302 (Oct. 2000; Conference presentation Jan. 19, 2000).
17-AAG <http://www.geldanamycin.com/17aag.htm> downloaded from the Internet Sep. 7, 2005.
Stebbins Cell, vol. 89, 239-250, 1997.
Lucas et al., Journal of Combinatorial Chemistry (2001), 3(6), 518-520 (Web Release Date: Sep. 21, 2001).
Basso et al., Akt forms and intracellular complex wih heat shock protein 90 (Hsp90) and cdc37 and is destabilized by inhibitors of . . . , The Journal of Biological Chemistry, Oct. 18, 2002, pp. 39858-39866, vol. 277, No. 42, Publisher: The American Society for Biochemistry and Molecular Biology, Inc.
Bharadwaj et al., Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 in vivo, Molecular and Cellular Biology, 1999, pp. 8033-8041, vol. 19, No. 12, Publisher: American Society for Microbiology.
Chene, ATPases as drug targets: learning from their structure, Nature Reviews, 2002, pp. 665-673, Publisher: Nature Publishing Group.
Chiosis et al., A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth . . . , Chemistry & Biology, 2001, pp. 289-299, Publisher: Elsevier Science Ltd.
Jez et al., Crystal structure and molecular modeling of 17-DMAG in complex with human hsp90, Chemistry & Biology, 2003, pp. 361-368, vol. 10, Publisher: Elsevier Science Ltd.
Maloney et al., HSP90 as a new therapeutic target for cancer therapy: the story unfolds, 2002, pp. 3-24, Publisher: Ashley Publications, Published in.
Roe et al., Structural basis for inhibition of the hsp90 molecular chaperone by the antibiotics radicicol and geldanamycin, J. Med. Chem, 1999, pp. 260-266, vol. 42, Publisher: American Chemical Society.
Rui et al., Chemistry and pharmacology of new potent analgesic epibatidine, 1999, pp. 313-326, vol. 11, No. 3, Published in: Shanghai, China.
Schulte et al., Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association, The Journal of Biological Chemistry, Oct. 13, 1995, pp. 24585-24588, vol. 270, No. 41.
Schulte et al., Antibiotic radicicol binds to the N-terminal domain of hsp90 and shares important biologic activities with geldanamycin, Cell Stress & Chaperones, 1998, pp. 100-108, Publisher: Harcourt Brace and Co Ltd.
Stebbins et al., Crystal Structure of an Hsp90-Geldanamycin Comples: Targeting of a Protein Chaperone by an Antitumor Agent, Molecular Biology, Apr. 18, 1997, pp. 239-250, vol. 89.
Xu et al., Sensitivity of mature ErbB2 to geldanamycin is conferred by its kinase domiain and is mediated by the chaperone protein , The Journal of Biological Chemistry, Feb. 2, 2001, pp. 3702-3708, vol. 276, No. 5.
Zou et al., Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 Complex) that forms a stress-sensitive . . . , Cell, Aug. 21, 1998, pp. 471-480, vol. 94, Publisher: Cell Press.
Black et al. “Reaction of Ninhydrin With Activated Anilines: Formation of Indole Derivatives.” Ietrahdron. 1994, vol. 50, No. 37, pp. 10983-10994. See Compound 17.
Kato et al. “Synthesis of Compounds Related to Antitumor Agents IV. On The Reaction of Aromatic Carboxylates With 2,4 Diamino-5-hydroxy-6-methylpyrimidine.” Chem. Pharm. Bull. 1076, vol. 24, No. 10, pp. 2461-2469. See Table 2.
Chavany, et al. “p185erbB2 Binds to GRP94 in Vivo”, Journal of Biological Chemistry, vol. 271, No. 9 Mar. 1, 1996, pp. 4974-4977.
Neckers, “Effects of Geldanamycin and Other Naturally Occurring Small Molecule Antagonists of Heat Shock Protein 90 on HER2 Protein Expression”, Breast Disease 11 (2000) 49-59. pp. 49-59.
Schnur, et al. “erbB-2 Oncogene Inhibition by Geldanamycin Derivatives: Synthesis, Mechanism of Action, and Structure—Activity Relationships”, J. Med. Chem. 1995, 38, 3813-3820.
Stockwell, et al. High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications, Chemistry & Biology, Feb. 1999, 6:71-83.

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