Methods and compositions useful in treating cancer and reducing Wnt mediated effects in a cell
Inventors
Assignees
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Publication Number
US-9862714-B2
Publication Date
2018-01-09
Expiration Date
Abstract
Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.
Core Innovation
The invention provides compounds having a formula in which R2, R4, R5, R6, R7, and R8 are variable substituent groups selected from hydrogen, halogen, CN, CF3, substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The formula includes L1 selected as —NH—C(O)— or —C(O)—NH—, with z an integer from 1 to 4 and w an integer from 0 to 4, and an R6 attached to the phenyl ring para to the sulfonamide moiety.
The disclosure further describes sulfonamide/benzamide analogs and related scaffold variants with multiple substituent-variable options across R4 through R8 and related positions, together with substituted benzoic-acid/sulfonamide cores linked to heteroaryl amines. The described compounds include specific examples and intermediate structures, including benzamide and sulfone-linked structures featuring heteroaryl amine-derived moieties and varied sulfonyl substituents.
The document further relates these compounds to Wnt signaling inhibition and anti-proliferation activity. It describes reducing Wnt-mediated effects in cells, including increased degradation of Pygopus and beta-Catenin, decreased degradation of Axin, and decreased activities of Myc, CD44, Axin2, Bcl-9, and cyclin D, and it also reports evaluation in colorectal cancer cell lines with certain compounds showing anti-proliferation activity.
Claims Coverage
Independent claim coverage centers on a formula-defined compound with multiple variable substituents and linkage/position constraints, together with method and composition embodiments. The inventive features combine broad chemical scope with explicit biological use related to Wnt-mediated effects.
Defined compound formula with variable substituents
A compound having a specified formula in which R2, R4, R5, R6, R7, and R8 are independently selected from hydrogen, halogen, CN, CF3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, together with sulfonamide- and sulfonyl-related substituent options as defined by the claim.
Linkage moiety L1 with integer constraints
The formula includes L1 selected as —NH—C(O)— or —C(O)—NH—, with z an integer from 1 to 4 and w an integer from 0 to 4.
Para positioning of R6 on the phenyl ring relative to sulfonamide
An R6 is attached to the phenyl ring para to the sulfonamide moiety.
Reducing a Wnt-mediated effect by contacting cells
A method includes reducing a Wnt-mediated effect on a cell by contacting the cell with an effective amount of a compound recited in the identified claims.
Wnt-mediated effect defined by pathway component changes
The Wnt-mediated effect is defined as one or more of increased degradation of Pygopus and beta-Catenin, decreased degradation of Axin, and decreased activities of Myc, CD44, Axin2, Bcl-9, and cyclin D.
Pharmaceutical composition with a pharmaceutically acceptable excipient
A pharmaceutical composition includes a pharmaceutically acceptable excipient together with the compound identified in the specified compound claims.
Overall claim coverage includes a broadly defined compound family constrained by a specified core formula, L1 selection, integer parameters z and w, and a para positional requirement for R6 to the sulfonamide moiety. The coverage further includes method embodiments for reducing Wnt-mediated effects and pharmaceutical composition embodiments that include a pharmaceutically acceptable excipient.
Stated Advantages
Reduces a Wnt-mediated effect on a cell.
Increases degradation of Pygopus and beta-Catenin.
Decreases degradation of Axin.
Decreases activities of Myc, CD44, Axin2, Bcl-9, and cyclin D.
Certain compounds show anti-proliferation activity.
Documented Applications
Reducing a Wnt-mediated effect by contacting cells with an effective amount of the claimed compound.
Treating cancer in a subject by administering an effective amount of a disclosed compound.
Pharmaceutical compositions comprising the compound and a pharmaceutically acceptable excipient.
Evaluation in colorectal cancer cell lines using a cell-proliferation (viability) assay.
Cancer treatment.
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