Compounds for targeted protein degradation
Inventors
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Assignees
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624035-B2
Publication Date
2026-05-12
Expiration Date
Abstract
This disclosure provides a compound of formula (III):or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein the substituents are as defined herein. The disclosure also provides pharmaceutical compositions comprising said compounds and the use of said compounds in the treatment of diseases, e.g. cancer.
Core Innovation
The disclosure is directed to compounds, or pharmaceutically acceptable salts thereof, having defined structural frameworks and variants, including substituted -L-R2 moieties, broad R1 and R2 formula frameworks, multi-ring compound classes, and fluorinated, cyanoacrylamide-containing degrader scaffolds. It also includes compounds defined by multiple structural formulas, related variants, pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers, and salts including HCl and TFA salts.
The invention further relates to DCAF16 conjugates in which a DCAF16 protein is covalently bound to the compounds at a cysteine residue, and to a ternary complex involving DCAF16, DDB1, and BRD9. The disclosed content links these compounds to selective BRD9 degradation in comparison to BRD4 and to increased proteolysis, and also provides a complex multi-ring compound class with a fluoro-isopropyl dihydroisoquinoline core, a diazaspiro[2.5]octane-linked side chain, and substituted bicyclic heteroaryl substituents.
The compounds are described in the context of medicine to treat and/or prevent diseases associated with abnormal BRD9 activity, including cancer. The disclosure additionally provides explicit exclusions of specific named stereoisomer or derivative structures and characterization-related information for intermediates and compounds.
Claims Coverage
The consolidated claim coverage identifies multiple independent compound definitions across the provided items, with the recurring pattern of a compound, or a pharmaceutically acceptable salt thereof, defined by the disclosure’s structural framework. Across the provided material, the claims center on four recurring inventive features, with dependent refinement to a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
Defined compound framework with formula-based substituent restrictions
A compound, or a pharmaceutically acceptable salt thereof, defined by formula (I) or related formulas with specified substituent restrictions for variables such as R2, R3, and other ring-related groups.
Substituted -L-R2 moiety and broad R1/R2 framework
A compound, or a pharmaceutically acceptable salt thereof, having a substituted -L-R2 moiety with wavy line attachment and R6-R9 substituent choices, together with broad R1 and R2 formula frameworks and substituent constraints.
Fluorinated, cyanoacrylamide-containing degrader scaffold
A compound, or a pharmaceutically acceptable salt thereof, defined as a fluorinated, cyanoacrylamide-containing degrader scaffold associated with BRD9 selective degradation and increased proteolysis.
Multiring compound and pharmaceutically acceptable salt
A compound, or a pharmaceutically acceptable salt thereof, defined as a specific multi-ring compound structure.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the defined compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claim coverage centers on defined compound classes across the provided items, including formula-based compound/salt structures, substituted -L-R2 and R1/R2 frameworks, a fluorinated cyanoacrylamide degrader scaffold, and a multiring compound structure, with the recurring dependent refinement of a pharmaceutical composition containing a pharmaceutically acceptable carrier.
Stated Advantages
BRD9 selective degradation.
Increased proteolysis.
Selective degradation of BRD9 compared to BRD4 is described.
Proteomics is described as indicating preferential BRD9 degradation with minimal changes in other bromodomains.
In vivo tumor bioluminescence and survival effects are described.
Treat and/or prevent diseases associated with abnormal BRD9 activity, including cancer.
Documented Applications
Use in medicine to treat and/or prevent diseases associated with abnormal BRD9 activity, including cancer.
Cancer treatment by administering pharmaceutical compositions comprising the disclosed compounds with a pharmaceutically acceptable carrier.
Treating cancers using targeted protein degradation of BRD9.
Selective BRD9 degradation in cells or subjects.
BRD9/BRD4 degradation in cell assays and mechanistic/selectivity studies.
In vivo efficacy endpoints in luciferase-tagged MV4-11 and DFAM-68555 AML PDX models.
Cryo-EM characterization of a BRD9:DDA1:DCAF16:DDB1 ternary complex induced by Compound 9.
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