Compounds for treatment of cancer
Inventors
Li, Wei • Xiao, Min • Dalton, James • Ahn, Sunjoo • MILLER, Duane D • Wang, Jin
Assignees
University of Tennessee Research Foundation • Oncternal Therapeutics Inc
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Publication Number
US-11465987-B2
Publication Date
2022-10-11
Expiration Date
Abstract
The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.
Core Innovation
The invention relates to compounds represented by the structure of formula XXIII, with defined substituent chemistry and linkage or heteroatom options. The compound variables include R1, R2, R3, R4, R5, R6, R9, and R12, together with X and Y and integer parameters i, n, and m. The definitions include constraints that (R1)m, R2 and R3 collectively are not a single methyl group, and that R4, R5 and R6 cannot all be hydrogen.
The structure further defines R9 and R12 as hydrogen or substituted or unsubstituted alkyl, cycloalkyl, aryl, benzyl, haloalkyl, aminoalkyl, SO2-aryl, or (C(O))-aryl or OH-type options, with substitutions independently selected from a listed functional group set. X is defined as a bond or NH in some embodiments, and in other embodiments as NH, C1-C5 hydrocarbon, O, or S. Y is defined as C(O) and related carbonyl-, thiocarbonyl-, nitrogen-, and heteroatom-containing linkages as explicitly listed.
The patent text also includes pharmaceutically acceptable salts and, in some instances, hydrates, polymorphs, tautomers, metabolites, and stereoisomers. The broader record provides specific aryl-benzoyl imidazole, indolyl-benzoyl imidazole, ABI, RABI, and SMART compound examples, with characterization data and example compound series within the disclosed chemical families.
Claims Coverage
The consolidated record includes independent claims directed to formula XXIII compounds with extensive substituent definitions and structural constraints. Across the claims, the inventive coverage centers on variable groups at R1-R6, R9, and R12; linkage and heteroatom variables X and Y; integer ranges i, n, and m; and pharmaceutically acceptable forms. Some claim sets also include independent treatment claims directed to administering the defined compound to treat cancer, including drug-resistant tumors.
Formula XXIII compound with variable substituents and linkage parameters
A compound represented by the structure of formula XXIII wherein R1, R2, and R3 are independently selected from defined groups and collectively are not a single methyl group; R4, R5 and R6 are independently selected from defined groups with the constraint that R4, R5 and R6 cannot all be hydrogen; R9 and R12 are defined with listed substituent options; X is a bond or NH in some embodiments and NH, C1-C5 hydrocarbon, O, or S in other embodiments; Y is C(O) and related linkage options as explicitly listed; i is an integer within the stated range; n is an integer between 1-3; and m is an integer between 1-3, with pharmaceutically acceptable salt and, in some claims, hydrate, polymorph, tautomer, stereoisomer, or metabolite forms.
Treating cancer by administering the defined compound
A method of treating or suppressing cancer by administering a compound according to formula XXIII to a subject under conditions effective to treat the cancer, including treatment of drug-resistant tumors and, in dependent contexts, specified cancer types and metastatic melanoma.
The claims are directed to formula XXIII compounds with broad but constrained substituent scope, defined X and Y linkages, and stated integer ranges, optionally in pharmaceutically acceptable forms. The record also includes therapeutic claim coverage for administering the defined compounds to treat cancer, including drug-resistant tumors and specific cancer contexts.
Stated Advantages
Improved water solubility for an ABI (Aryl-Benzoyl-Imidazole) compound compared with a thiazole analog.
In vitro cell growth inhibition with IC50 values across prostate cancer and melanoma lines and MDR ovarian models.
Tubulin polymerization inhibition.
P-glycoprotein not a substrate behavior.
Addresses resistance, including drug resistance, as a strategy based on colchicine-binding site inhibition.
Aims to address neurotoxicity and solubility issues.
Provides therapeutic treatment, suppression, reduction, inhibition, and destruction of cancerous cells.
Anticancer potency is reported in cell-based evaluations, including IC50 values across multiple cancer cell lines.
Some compounds are reported to show circumvention of P-gp-mediated multidrug resistance or resistance index advantages in Pgp/MDR1-mediated contexts.
G2/M phase cell-cycle arrest and increased apoptosis are reported for selected compounds.
Dose-dependent tumor growth inhibition is reported in xenograft models.
Limited neurotoxicity is reported based on rotarod assessment.
No development of drug resistance after 21 days is reported in PC-3 tumors.
Vascular-disrupting and anti-endothelial activity is reported, including inhibition of capillary tube formation without disrupting preformed capillaries.
Increased endothelial monolayer permeability is reported.
Documented Applications
In vitro cell growth inhibition evaluation of the compounds against prostate cancer and melanoma cell lines and MDR ovarian models.
Water solubility determination for ABI (Aryl-Benzoyl-Imidazole) compounds.
Pharmacokinetic evaluation and MDR-related evaluation including P-glycoprotein non-substrate behavior and MDR factor/equipotency outputs.
Treating cancer and drug-resistant tumors, including drug resistant melanoma and drug resistant prostate cancer.
Treating metastatic melanoma tumors.
Administering the compound together with another cancer therapy.
Treating or suppressing cancer in a subject under conditions effective to treat the cancer.
Treating cancer selected from prostate cancer, breast cancer, ovarian cancer, skin cancer, melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNS cancer, or combinations thereof.
Prostate cancer and melanoma evaluations are reported using PC-3 and A375 cells, including G2/M arrest, apoptosis, and tubulin-related modeling and imaging.
Xenograft tumor models are used for PC-3 and A375 to assess tumor growth inhibition, neurotoxicity, and drug resistance outcomes.
Drug-resistance contexts are evaluated using P-glycoprotein-mediated multidrug resistance models and comparisons with vinblastine, vinca, and colchicine.
Anti-angiogenic and vascular-disrupting evaluation is described for compounds 17ya and 55, including capillary tube formation inhibition and endothelial permeability assays.
Pharmaceutical compositions containing the disclosed compounds are described.
In vitro and cellular cytotoxicity testing is described using an SRB cytotoxicity assay and cancer cell lines including LNCaP, DU 145, PC-3, PPC-1, A375, WM-164, OVCAR-8, and NCI/ADR-RES.
In vivo and drug-like property discussion is reported for representative ABI/RABI analogs, including pharmacokinetics, metabolic stability, and tumor xenografts.
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