Methods and compositions useful in treating cancer and reducing WNT mediated effects in a cell
Inventors
Assignees
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Publication Number
US-9416101-B2
Publication Date
2016-08-16
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 concerns compounds defined by a structural formula in which L1 is selected as —NH—C(O)— or —C(O)—NH—. The substituent variables include R2, R4, R5, R6, R10, R11, and R12, with additional substituent positions and functional groups as expressed in the formula, and R2 and R5 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
The core structural framework is further parameterized by integer variables z and w, each being an integer from 0 to 4. In the disclosed examples, the series is implemented with sulfonamide/sulfone-linked benzamide derivatives, including substituted indoline/dihydroquinoline or benzoic-acid bearing sulfonyl groups, followed by formation of downstream benzamide derivatives bearing heteroarylamines such as 4-(pyridin-2-yl)thiazol-2-amine and other anilines/heterocycles.
The patent further links these compounds to reducing Wnt-mediated effects and to treating cancers, and it includes pharmaceutical compositions comprising a compound with pharmaceutically acceptable excipients and pharmaceutically acceptable salts. The disclosure also reports cell-proliferation/viability assay context and anti-proliferation activity for certain compounds in colorectal cancer cell lines.
Claims Coverage
The provided claim set centers on one independent claim directed to a compound defined by a structural formula with multiple independently selected substituent variables and integer parameters z and w. The coverage also includes an optional connectivity condition joining R2 and R5, and a pharmaceutical composition context comprising a pharmaceutically acceptable excipient.
Compound defined by a variable substituent formula
A compound having a formula wherein L1 is —NH—C(O)— or —C(O)—NH—; R2, R4, R5, R6, R10, R11, and R12 are independently selected from hydrogen, halogen, —CN, —CF3, substituted or unsubstituted alkyl/heteroalkyl/cycloalkyl/heterocycloalkyl/aryl/heteroaryl, and additional amide/carbonyl/ether/sulfonamide/sulfamoyl/sulfonyl/thio-related substituents as expressed in the claim.
Integer parameters z and w for structural variation
The compound where z is an integer from 0 to 4 and w is an integer from 0 to 4.
Optional joining of R2 and R5 to form a heterocycle or heteroaryl
R2 and R5 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the claimed formula family.
Coverage centers on a structurally defined compound class with a selectable amide-type linker L1, extensive substituent selection including sulfonamide, sulfamoyl, sulfonyl, and related thio/ether/carbonyl groups, integer constraints z and w each ranging from 0 to 4, and an optional connectivity condition joining R2 and R5. Further coverage extends to a pharmaceutical composition including a pharmaceutically acceptable excipient.
Stated Advantages
Reducing Wnt-mediated effects.
Treating cancers.
Certain compounds show anti-proliferation activity.
Documented Applications
Reducing Wnt-mediated effects using biomarkers including Pygopus, non-oncogenic beta-catenin, Axin, Myc, CD44, Axin2, Bcl-9, and cyclin D.
Cancer treatment.
Administration of pharmaceutical compositions comprising the compound with pharmaceutically acceptable excipients and pharmaceutically acceptable salts.
Cell-proliferation/viability assay in colorectal cancer cell lines, reporting anti-proliferation activity for certain compounds.
Reducing Wnt-mediated effects in cells.
Treating cancer in a subject.
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