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Diglycidic ether derivative therapeutics and methods for their use

A compound, alkyl technology, applied in the field of cancer therapy and treatment, can solve problems hindering virtual docking drug development methods, etc.

Active Publication Date: 2011-06-01
BRITISH COLUMBIA CANCER AGENCY BRANCH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although the crystal structure of the AR C-terminal LBD has been solved, the crystal structure of NTD has not been solved because of its high flexibility and intrinsic disorder in solution (Reid et al. 2002 J. Biol. Chem. (Biochemical Journal )277, 20079-20086), thus hindering virtual docking drug discovery approaches

Method used

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  • Diglycidic ether derivative therapeutics and methods for their use
  • Diglycidic ether derivative therapeutics and methods for their use
  • Diglycidic ether derivative therapeutics and methods for their use

Examples

Experimental program
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Embodiment 1

[0204] A number of screening applications are used to identify active compounds that inhibit AR NTD activity. The initial screen was a cell-based assay involving LNCaP cells maintained in culture. The assay consists of AR activation using both androgen (ligand-dependent) and forskolin (ligand-independent) and measuring the level of PSA secreted by LNCaP cells in the presence and absence of crude extract . PSA is an androgen-regulated gene containing several well-characterized AREs. Androgen-independent increase in PSA gene expression occurs through an AR-dependent mechanism in prostate cancer cells. PNG01-185 extract was observed to block PSA secretion induced by both androgen and forskolin.

[0205] To ensure that the inhibitory effect of PNG 01-185 extract on endogenous PSA protein was at the transcriptional level, reporter gene constructs were also investigated. Activation of endogenous AR was measured in LNCaP human prostate cancer cells by measuring an androgen-respon...

Embodiment 2

[0217] The purified active compound from the extract described in Example 1 was isolated. Geodia lindgreni (Lendenfeld, 1903) samples were collected by hand using SCUBA at a depth of 5 M below the rocks on a sheltered reef off Loloata Island, Papua New Guinea. The frozen sponge (890 g) was then exhaustively extracted with MeOH and the crude extract was observed to be active in the assay described in Example 1 above. Bioassay-guided fractionation provided purified samples PNG01-185-017-2, -5, -6, -7 and -8 ( figure 2 ). The structure has been elucidated by analysis of NMR and MS data, which are shown in Example 1 above.

Embodiment 3

[0220] Compounds were identified by applying secondary screening. Purified compounds were tested for their ability to inhibit: transactivation of the androgen receptor N-terminal domain (AR NTD); other steroid receptors (specificity); endogenous expression of PSA mRNA; interaction; N / C interaction; and proliferation of prostate cancer cells in response to androgens.

[0221] Transactivation of the AR NTD

[0222] In the absence of serum and androgens, both forskolin (FSK) and IL-6, which stimulate PKA activity, increase PSA gene expression in prostate cancer cells through a mechanism involving AR NTD transactivation (Sadar, M.D., J.Biol.Chem. 274, 7777-7783 (1999); Ueda, T., Bruchovsky, N., Sadar, M.D., J.Biol.Chem. 277, 7076-7085 (2002); Ueda, T., Mawji, N.R., Bruchovsky, N., Sadar, M.D., J. Biol. Chem. 277, 38087-38094 (2002B); Quayle SN, Mawji NR, Wang J , Sadar M.D., Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1331-6.). The ability of 185-9-2 to inhibit transactivatio...

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Abstract

The present invention provides compound having a structure of Formula I or Formula II. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 61 / 129,537, entitled "Small Molecule Therapeutics and Methods of Using Them," filed July 2, 2008, which is hereby incorporated by reference in its entirety . [0003] Statement Regarding Federally Funded Research [0004] This invention was made in part with government support under Grant No. W81XWH-05-1-0058 (PC040768) awarded by the U.S. Army Medical Research and Materiel Command. The Government has certain rights in this invention. technical field [0005] The present invention relates to therapeutic agents, their use and methods of treatment for various indications, including various cancers. In particular, the present invention relates to therapies and methods of treatment of cancer, such as prostate cancer, including all stages and androgen-dependent, androgen-sensitive and androgen-independent (also known as hormone-refractory...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/295A61K31/09A61K31/225A61P35/00A61P5/28C07C229/06
CPCC07C229/12A61K31/09C07C39/367A61K31/225C07C43/23C07B2200/07A61P13/08A61P15/00A61P15/08A61P17/00A61P17/02A61P17/10A61P17/14A61P27/02A61P35/00A61P43/00A61P5/24A61P5/28C07C229/06C07B55/00
Inventor 玛丽安娜·D·萨达尔纳斯林·R·穆基王军雷蒙德·J·安德森戴维·E·威廉姆斯迈克·勒布朗
Owner BRITISH COLUMBIA CANCER AGENCY BRANCH
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