UBE2K modulators and methods for their use
Inventors
VISHNUDAS, VIVEK K. • Chimmanamada, Dinesh U. • Khedkar, Santosh A.
Assignees
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Publication Number
US-11091447-B2
Publication Date
2021-08-17
Expiration Date
Abstract
Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating conditions associated with modulation of UBE2K.
Core Innovation
The invention relates to compounds defined by a Formula and to pharmaceutically acceptable salts of the compounds. The disclosed compound series includes benzamide/heteroaryl substituted molecules having a common core with fluorinated methoxy groups and variable aromatic substituents, including triazole-series and pyrazole-series sulfonamide benzamides, and the disclosure provides compound-specific characterization datasets and corresponding chemical structures for these Formula-defined compounds.
The disclosed subject matter includes UBE2K modulators, and reports that the inventive compounds stabilize Mono-Ub UBE2K and reduce poly-ubiquitin product. The content further reports UBE2K selectivity over other E2 conjugating enzymes, modulation of Praja1-linked ubiquitin discharge/poly-ubiquitination, and tumor growth inhibition data from xenograft point-of-concept studies.
The disclosure also provides detailed chemical structure depictions and synthetic preparation examples and intermediates for multiple related carboxamide-like compounds, including substituted pyrazole scaffolds, benzamide derivatives, and triazole-containing compounds. The content includes representative compound examples, reported LC-MS and NMR data, and analogous difluoromethoxy variants and related table compounds.
Claims Coverage
The independent claim coverage is broadly directed to Formula-defined compounds or a specific chemical Formula, including pharmaceutically acceptable salts, and separately to pharmaceutical compositions including that compound plus a pharmaceutically acceptable carrier. Across the independent claims, the inventive features are the Formula-defined compound and the optional pharmaceutically acceptable salt form, with the composition claim further requiring a carrier.
Formula-defined compound and pharmaceutically acceptable salt
A compound defined by the Formula, or a pharmaceutically acceptable salt of the compound.
Pharmaceutical composition with formula-defined compound and carrier
A pharmaceutical composition comprising a compound defined by the Formula, or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable carrier.
Claim coverage centers on Formula-defined compounds, optionally as pharmaceutically acceptable salts, and extends that scope to pharmaceutical compositions containing the Formula-defined compound and a pharmaceutically acceptable carrier.
Stated Advantages
Stabilize Mono-Ub UBE2K.
Reduce poly-ubiquitin product.
Exhibit UBE2K selectivity over other E2 conjugating enzymes, including UBE2D4, UBE2E1, UBE2Q2, UBE2S, and UBE2W.
Modulate Praja1-linked ubiquitin discharge/poly-ubiquitination.
Show tumor growth inhibition in xenograft point-of-concept studies.
Documented Applications
Use in biochemical/cellular contexts to stabilize Mono-Ub UBE2K and reduce poly-ubiquitin product, with effects assessed in cellular models including MIA PaCa-2, K-562, and MV.4.11.
In vivo xenograft point-of-concept studies showing tumor growth inhibition, with reference models including SCID Bg mice and nude mice.
Treating cancer via UBE2K modulation through inhibition of UBE2K activity.
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