Compounds for treatment of cancer
Inventors
Miller, Duane D. • Chen, Jianjun • Dalton, James T. • Li, Chien-Ming • Ahn, Sunjoo • Li, Wei
Assignees
University of Tennessee Research Foundation • Oncternal Therapeutics Inc
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Publication Number
US-10865196-B2
Publication Date
2020-12-15
Expiration Date
Abstract
The present invention relates to a compound of formula XXII and a compound of formula 17ya, which are defined as anywhere in the specification, to a composition comprising the same, and to a method of using thereof in the treatment of various forms of cancer.
Core Innovation
The invention concerns substituted indolyl-imidazole methanones and related indolyl-substituted imidazolyl (3,4,5-trimethoxyphenyl)methanone compounds, including the indol-1-yl, indol-2-yl, indol-4-yl, indol-5-yl, indol-6-yl, and indol-7-yl variants, together with pharmaceutically acceptable salts, hydrates, and combinations thereof. The compounds are described as anti-cancer compounds and as substituted methanones with an indolyl-containing motif connected to an imidazol-4-yl group and a (3,4,5-trimethoxyphenyl)methanone moiety.
The disclosure presents the compounds as having anticancer activity and as capable of treating cancer by administering a therapeutically effective amount. It includes prevention/treatment of diverse cancers, including prostate, breast, ovarian, melanoma, lung, colon, leukemia, renal, and CNS cancers, including drug-resistant and metastatic cancer.
The document further reports anti-tubulin activity, equipotent activity in OVCAR-8 and NCI/ADR-RES, P-gp-independent behavior, and a dose-dependent tubulin inhibition in an in vitro microtubule polymerization assay. It also states competition for the colchicine-binding site, induction of apoptosis, metabolic stability, permeability, aqueous solubility, a CYP inhibition profile, pharmacokinetics information, BBB penetration data, and in vivo xenograft efficacy in prostate and MDR models.
Claims Coverage
The consolidated claim set covers a selected group of specific substituted methanone compounds and a method of treating cancer by administering those compounds at a therapeutically effective amount. The inventive features center on the specific indolyl-substituted imidazolyl methanone scaffold and its use as an anti-cancer therapeutic, with dependent features further constraining dosing, administration conditions, cancer types, and combination therapy.
Indolyl-substituted imidazolyl methanone selection
A compound selected from the group of (2-(1-H-indol-1-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; (2-(1-H-indol-2-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; (2-(1-H-indol-4-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; (2-(1-H-indol-5-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; (2-(1-H-indol-6-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; and (2-(1-H-indol-7-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone, or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a combination thereof.
Cancer treatment by administering a therapeutically effective amount
A method of treating cancer by administering a therapeutically effective amount of a compound selected from the group of the specified indolyl-substituted imidazolyl methanones, or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a combination thereof.
Therapeutically effective dosing by body weight range
The method administers the compound in a range of about 0.01 mg to about 100 mg per kg of body weight.
Administration via specified routes or direct-site administration
The method provides for administering the compound via enumerated administration routes and includes administering the compound directly to a site containing cancer cells.
Cancer selection among enumerated cancer types
The method uses the cancer selected from prostate cancer, breast cancer, ovarian cancer, skin cancer, lung cancer, colon cancer, leukemia, renal cancer, or CNS cancer, or a combination of these.
Combination treatment with another cancer therapy
The method administers the compound together with another cancer therapy.
Overall, the claim coverage centers on administering therapeutically effective amounts of selected indolyl-substituted imidazolyl methanone compounds for treating cancer, with dependent features specifying dosing range, administration routes and direct-site administration, enumerated cancer types, and combination therapy with another cancer therapy.
Stated Advantages
Selected compounds are reported to show equipotent antiproliferative activity in OVCAR-8 and NCI/ADR-RES (P-gp overexpressing) cells, suggesting P-gp-independent action.
Treating cancer.
Destroying cancerous cells.
Inhibiting tumor vascularization.
Inhibiting endothelial cell growth.
Targeting drug-resistant tumors.
Reducing the risk of cancer.
Suppressing cancer.
Circumvention of P-gp-mediated multidrug resistance with equipotent activity versus paclitaxel/docetaxel-resistant cells.
Inhibition of tumor growth in prostate and MDR xenograft models, including improved effectiveness versus docetaxel.
BBB penetration described as brain/plasma ratio and reported blood-brain barrier (BBB) penetration data.
Vascular disrupting activity described as inhibition of HUVEC capillary formation and increased endothelial monolayer permeability.
Mechanistic activity involving competition for the colchicine-binding site and inhibition of porcine brain tubulin polymerization.
Drug-like properties described as metabolic stability, permeability, aqueous solubility, and a CYP inhibition profile.
An unexpected lack of prostate cancer activity is reported for phenyl amino imidazole analog (5-e) relative to related phenyl amino thiazole analogs (5-a/5-Hb/5-c/5-d).
Documented Applications
Antiproliferative/cancer cell testing in OVCAR-8 and NCI/ADR-RES (P-gp overexpressing) cells, including an anti-tubulin/p-gp context.
Prostate cancer cell lines (LNCaP, PC-3, DU-145, PPC-1) are referenced in the disclosure for activity/inactivity observations.
Cancer treatment by administering the compound group, including cancers selected from prostate cancer, breast cancer, ovarian cancer, skin cancer, lung cancer, colon cancer, leukemia, renal cancer, or CNS cancer, or a combination of these.
Treating metastatic melanoma, prostate cancer, ovarian cancer, uterine cancer, CNS cancer, and other cancers selected from prostate, breast, ovarian, skin, lung, colon, leukemia, renal, or CNS cancers.
Treatment of drug-resistant tumors.
Cancer treatment by using the compound in combination with another cancer therapy.
In vivo xenograft treatment efficacy for prostate and MDR models, including tumor growth inhibition and improved effectiveness versus docetaxel.
Activity against P-gp-mediated multidrug resistance, including testing in paclitaxel/docetaxel-resistant cell models.
Use related to BBB penetration as described by brain/plasma ratio and BBB penetration data.
Use related to vascular disrupting activity, described through HUVEC capillary formation inhibition and endothelial monolayer permeability increase.
Mechanism-anchored application of tubulin inhibition through colchicine-binding site competition and tubulin polymerization inhibition, with induction of apoptosis.
Antiproliferative activity testing across cancer cell lines using IC50 (±SEM) values, including OVCAR-8 and NCI/ADR-RES for anti-tubulin compounds, and additional cell lines including LNCaP, PC-3, DU 145, PPC-1, A375, B16-F1, and WM164.
Use of the compounds in a method of treating cancer by administering a therapeutically effective amount, including specified cancer types such as prostate cancer, breast cancer, ovarian cancer, skin cancer, lung cancer, colon cancer, leukemia, renal cancer, or CNS cancer, or combinations.
Use of the specified compounds in combination with another cancer therapy.
Mechanistic evaluation by cell-cycle analysis and an in vitro microtubule polymerization assay using bovine brain tubulin.
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