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Thiohydantoin androgen receptor antagonists for the treatment of cancer

A technology of sulfo-receptor, which is applied in the direction of antineoplastic drugs, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problem of tumor growth without compounds

Inactive Publication Date: 2019-08-23
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In vitro reporter assays confirmed resistance and demonstrated both compound and agonist conversion in tumors engineered to express AR F876L, neither compound controlling tumor growth

Method used

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  • Thiohydantoin androgen receptor antagonists for the treatment of cancer
  • Thiohydantoin androgen receptor antagonists for the treatment of cancer
  • Thiohydantoin androgen receptor antagonists for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment

[0374]The preparation of compounds of the present invention can be found in U.S. Patent Application No. 13 / 579,009, filed February 16, 2011, entitled "Androgen Receptor Modulators and Uses Thereof," which claims the February 2010 The benefit of U.S. Provisional Patent Application No. 61 / 305,082 filed on the 16th, which is hereby incorporated by reference.

[0375] biological example

[0376] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or its extracts.

[0377] Antagonism of receptors in biological samples can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays, gene expression studies, and biological target identification.

[0378] Certain embodiments of the invention relate to methods of treatment...

Embodiment 1

[0385] Compounds bind to radioligands for AR, GR, and ER

[0386] Radioligand binding assays were performed using cell extracts and ligands as described below. Complete methods are included in the cited publications. K d Values ​​were determined by non-specific incubation assays.

[0387] receptor

[0388] GR (human) (agonist radioligand) IM-9 cells (cytosol)

[0389] [ 3 H] Dexamethasone 1.5nM 1.5nM triamcinolone acetonide (10 μM) 6h 4°C scintillation counting (Clark, A.F et al., (1996) Invest. Ophtalmol. Vis. Sci., 37:805-813).

[0390] ER (non-selective) (human) (agonist radioligand) MCF-7 cells (cytosol)

[0391] [ 3 H] Estradiol 0.4nM 0.2nM 17-β-estradiol (6μM) 20h 4°C scintillation counting (Parker, G.J et al. (2000) J.Biomol.Screen., 5:77-88).

[0392] AR (human) (agonist radioligand) LNCaP cells (cytosol)

[0393] [ 3 H] Methyltrienone 1nM 0.8nM Mibolone (1μM) for 24 hours, scintillation counting at 4°C.

[0394] Zava, D.T et al. (1979) Endocrinology, 10...

Embodiment 2

[0406] Antagonism of AR (WT or F876L) reporter assays

[0407] LNCaP AR(cs) and LNCaP F876L luciferase cell lines were generated by transduction of each cell line (Description of cell line generation Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, ManevalEC, Chen I, Darimont B, Hager JH. Clinically relevant androgen receptor mutations confer resistance to second-generation antiandrogens enzalutamide and ARN-509. Discovering Tumors (Cancer Discov 2013;3:1020-1029) , which has an androgen response element firefly luciferase lentiviral construct with an MOI (multiplicity of infection) of 50, following the manufacturer's instructions (Qiagen). Stable mixed population cell lines were generated using puromycin (Life Technologies) selection at 1:10,000 v / v. The following protocol was used for both cell lines and for testing compounds of formula (I) of the present invention.

[0408] LNCaP cells were grown to approximately 80% confluency, media removed and cell...

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Abstract

Disclosed are compounds, compositions and methods for treating and / or ameliorating diseases, syndromes, disorders, or conditions associated with AR mutant receptors linked to castration-resistant prostate cancer, in a subject, including a mammal and / or human, in need thereof, who has demonstrated resistance to a first or second generation AR antagonist, comprising, consisting of, and / or consistingessentially of, administering to a subject in need thereof, a therapeutically effective amount of a compound falling within the scope of Formula (I).

Description

[0001] Cross References to Related Applications [0002] U.S. Patent Application No. 13 / 579,009, filed February 16, 2011, entitled "Androgen Receptor Modulators and Uses Thereof," is hereby incorporated by reference - U.S. Nonprovisional Application No. 13 / 579,009, claimed on February 16, 2010 Benefit of filed U.S. Provisional Patent Application No. 61 / 305,082. technical field [0003] The present invention relates to compounds of formula (I) as defined herein for use in the treatment and / or amelioration of castration-resistant prostate cancer-associated AR mutant receptor-associated diseases in subjects in need thereof, Use for a syndrome, disorder or condition. Background technique [0004] Prostate cancer is the most common non-cutaneous malignancy in men and the second leading cause of cancer death in the Western world. As a male sex organ, the development of the prostate is highly regulated by the products of androgen, AR, and androgen-dependent genes. During all sta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K31/4545A61K31/496A61K31/497A61K31/506A61K31/5377A61P35/00
CPCA61K31/4545A61K31/496A61K31/497A61K31/506A61K31/5377A61K31/444A61K31/4725A61K31/4439A61P13/08A61P35/00A61P43/00A61K31/4178
Inventor G·C·比格南J·布兰奇P·J·康诺利L·B·T·埃斯高拿I·希克森L·米亚波尔V·潘德C·罗科波张筑明
Owner JANSSEN PHARMA NV