Pharmaceutically active pyrazolo-pyridone modulators of DCN1/2-mediated cullin neddylation
Inventors
Kim, Hoshin • Guy, Rodney Kiplin • HAMMILL, Jared T. • SCOTT, Daniel Charles • Schulman, Brenda Arlene • Singh, Bhuvanesh
Assignees
St Jude Childrens Research Hospital • University of Kentucky Research Foundation • Memorial Sloan Kettering Cancer Center
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Publication Number
US-12409171-B2
Publication Date
2025-09-09
Expiration Date
Abstract
A DCN1/2-mediated cullin neddylation modulator; a method for treating disorders associated with dysfunctional DCN1 and/or UBC12, Alzheimer's disease, other neurodegenerative diseases, bacterial infections, or viral infections; and a method for treating cancers are provided. The DCN1/2-mediated cullin neddylation modulator includes a compound according to Formula I disclosed herein. The methods include administering to a mammal a therapeutically effective amount of a compound according to Formula I. Also provided herein is a pharmaceutical composition including a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Core Innovation
The invention relates to DCN1/2-mediated cullin neddylation modulators according to Formula I. The modulator comprises variable substituents R1, R2, R3, R4, R5, R6, and R7, together with X, Linker, Y, Z, and an integer n from 0 to 20. The structure allows broad substitution across alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, haloaryl, alkyl ester, alkyl carboxylic acid, alkyl amide, and cyanomethyl classes, while preserving the DCN1/2-mediated cullin neddylation modulator scaffold.
R3 is selected from NHC(=O)-R6, NHC(=O)-NH-R6, NHSO2-R6, C(=O)-NH-R6, or CH2C(=O)-R6, and X is selected from O, NH, S, or Linker. Linker is selected from (OCH2CH2)n-(PEG), alkyl linker, or aminoalkyl linker, each Y is independently selected from CH2, NH, O, or S, Z is (OCH2CH2)n, alkyl linker, or aminoalkyl linker, and each n is independently an integer from 0 to 20. R5 is H or biotin, and R7 includes a -Y-Z-Y-R8 motif.
The disclosed examples comprise substituted small-molecule compounds within the Formula I family, including chiral pyrazolo[3,4-b]pyridine or pyrazolo-pyridone-based structures and substituted benzamide, urea, or carboxamide linkages. The examples vary aryl and heteroaryl substituents, stereochemistry, and linker or side-chain functionality, and are accompanied by analytical characterization such as 1H NMR and HRMS/LRMS. The compounds are presented as DCN1/2-mediated cullin neddylation modulator compounds and as members of the Formula I scaffold.
Claims Coverage
The claim coverage is anchored on one independent Formula I DCN1/2-mediated cullin neddylation modulator with broad substituent definitions, narrowed by cis geometry, non-identity of R1/R2/R4, and biotin-containing nested linker motifs, and extended to pharmaceutical compositions and mammalian administration. In total, the claims present 6 inventive features.
Formula I DCN1/2-mediated cullin neddylation modulator
A DCN1/2-mediated cullin neddylation modulator according to Formula I, with R1, R2, R3, R4, R5, R6, and R7 defined by the specified substitution sets; X selected from O, NH, S, or Linker; Linker selected from (OCH2CH2)n-(PEG), alkyl linker, or aminoalkyl linker; each Y independently selected from CH2, NH, O, or S; Z selected from (OCH2CH2)n, alkyl linker, or aminoalkyl linker; and each n independently an integer from 0 to 20.
R3 carbonyl- and sulfonyl-containing motif
R3 is selected from NHC(=O)-R6, NHC(=O)-NH-R6, NHSO2-R6, C(=O)-NH-R6, or CH2C(=O)-R6.
Biotin-containing R5 and nested linker motif
R5 is H or biotin, and R7 includes a -Y-Z-Y-R8 motif.
Cis geometry constraint
R3 and R4 each have a cis geometry.
Distinctness constraint for R1, R2, and R4
R1, R2, and R4 are not identical to each other.
Pharmaceutical composition and mammalian administration
A pharmaceutical composition includes a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier; and a mammal is administered a therapeutically effective amount of the compound to ameliorate disorders associated with dysfunctional DCN1 and/or UBC12, including Alzheimer’s disease, other neurodegenerative diseases, bacterial infections, or viral infections.
The claim coverage centers on a Formula I DCN1/2-mediated cullin neddylation modulator with broad substituent freedom, refined by cis geometry, non-identity of R1/R2/R4, and biotin-containing nested linker motifs, and extended to pharmaceutical compositions and therapeutic administration for specified DCN1/UBC12-related disorders and infections.
Stated Advantages
Amelioration of disorders associated with dysfunctional DCN1 and/or UBC12.
Amelioration in disease contexts including Alzheimer’s disease and other neurodegenerative diseases.
Amelioration in bacterial and viral infection contexts.
Unexpected potency increases.
Improved oral bioavailability.
Isoform selectivity: inhibition of NEDD8 transfer for DCN1 and DCN2 with no inhibition reported for DCN3/4/5.
Selective inhibition in cells: selective inhibition of steady-state Cul1 and Cul3 neddylation in HCC95 cells.
Substantially more potent cis geometry across the pyridine ring than corresponding trans geometry.
Improved potency and/or oral bioavailability from substituent effects at R2, R5, and R6.
Improved binding/target selectivity and therapeutic index derived from two chiral centers and cis geometry.
Reduction of Cul1/Cul3 neddylation in cancer cells.
Probe utility via DCN1/UBC12 engagement.
Highly selective for DCN1/2 over DCN3/4/5.
Improved potency versus the hit compound.
Potency increases for para-fluoro substitution versus an unsubstituted benzene ring.
Meta/para difluoro substitution retains activity relative to meta-fluoro alone.
Partial activity rescue is observed for an inactive isosteric pyridine analog when an added para-fluoro substituent is present.
Documented Applications
Therapeutically effective administration to a mammal to ameliorate disorders associated with dysfunctional DCN1 and/or UBC12, including Alzheimer’s disease, other neurodegenerative diseases, bacterial infections, or viral infections.
Pharmaceutical composition use with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Biochemical and cellular evaluation of DCN1/UBC12 modulator analogs, including TR-FRET binding assay assessment and steady-state Cul1/Cul3 neddylation in HCC95 cells.
Structural validation via an X-ray co-crystal structure with DCN1 to confirm a binding mode.
Modulating DCN1/UBC12-mediated cullin neddylation as a cancer cell target, including reduction of Cul1/Cul3 neddylation in cancer cells.
Use as chemical probes or chemical tools related to DCN1/UBC12 engagement.
Pulse-chase assays to measure DCN1/2 inhibition and selectivity over DCN3/4/5.
Immunoblot-based analysis of reduced steady-state Cul1/Cul3 neddylation in HCC95 cells.
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