BRD9 degraders and uses thereof
Inventors
Ruppel, Sabine K. • Yang, Zhaoxia • LOWE, Jason T. • Voigt, Johannes H. • Netherton, Matthew • Brucelle, Francois
Assignees
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Publication Number
US-11787800-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancers and viral infections.
Core Innovation
The invention relates to a compound having the structure of Formula I, where a linker having the structure of Formula II is joined to a degradation moiety B having the structure of Formula A and an A substructure having the structure of Formula III. The linker includes A1-E1-F-E2-A2, with A1 a bond between the linker and A, A2 a bond between B and the linker, E1 and E2 independently absent, CH2, O, or NCH3, and F optionally substituted C2-10 heterocyclylene.
Formula III defines extensive variable substituents and ring systems, including R1, Z1/R2, X1, X2, X3, X4, G3/G′, and additional R-group options. The disclosure specifies X1 as N and X2 as C—R7, with R7 defined by selected optionally substituted alkyl, heteroalkyl, alkoxy, amino, sulfone, sulfonamide, carbocyclyl, and heterocyclyl groups, and includes optional cyclization of substituent pairs to form carbocyclyl or heterocyclyl ring systems.
The compound definition further permits extensive substitution on the A and degradation-moiety portions, including RA1, RA2, RA3, RA4, RA5, RA6, RA7, and RA8-type variables, with optional combinations that form larger ring systems and pharmaceutically acceptable salts. The disclosure also presents structural variants and exemplified compound members within the same Formula I framework.
Claims Coverage
The claim coverage centers on one independent Formula I compound claim and dependent claims that refine structural variables and method-of-use subject matter. The inventive coverage includes the linked Formula I scaffold and at least two method claims for BRD9 inhibition and oral administration.
Formula I compound with linker and degradation moiety architecture
A compound having the structure of Formula I, with L having the structure of Formula II and B being a degradation moiety having the structure of Formula A, and A having the structure of Formula III.
Linker structure with E1, E2, and heterocyclylene F
L has the structure A1-E1-F-E2-A2, where each of E1 and E2 is independently absent, CH2, O, or NCH3, and F is optionally substituted C2-10 heterocyclylene.
Formula III substituent and ring-system definitions
A has the structure of Formula III with R1, Z1/R2, X1/X2, X3/X4, G3/G′, and related substituent options, including X1 being N, X2 being C—R7, and optional cyclization of substituent pairs to form ring systems.
Optional pharmaceutically acceptable salts
The compound scope includes pharmaceutically acceptable salts thereof.
BRD9 inhibition method using the Formula I compound
A method for inhibiting the level and/or activity of BRD9 in a subject by administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, where BRD9 is defined by at least 85% sequence identity to the amino acid sequence encoded by the BRD9 gene nucleic acid sequence.
Oral administration of the BRD9 inhibitor compound or composition
The method further includes administering the compound or a pharmaceutical composition orally.
Overall, the claims define a Formula I compound built from a Formula II linker and a Formula A degradation moiety containing a Formula III A substructure, with extensive but explicitly bounded substituent and cyclization options. The claim set also includes BRD9 inhibition use claims with an explicit sequence-identity definition for BRD9 and an oral administration option.
Stated Advantages
Depletion of BRD9 is described as reducing the SS18-SSX fusion protein in synovial sarcoma.
The disclosure states that BRD9/BAF complex involvement relates to cancers.
The disclosure states that BRD9/BAF-related activity relates to antiviral activities.
Provides cell-based BRD9 degradation potency support using a BRD9-NanoLuc degradation assay, with many compounds showing IC50 <1 μM.
Documented Applications
Use of the disclosed Formula I compounds to inhibit the level and/or activity of BRD9 in a subject.
Oral administration of the compound or a pharmaceutical composition as part of the BRD9 inhibition method.
Synovial sarcoma, where BRD9 depletion reduces the SS18-SSX fusion protein.
Cancer, where BRD9/BAF complex involvement is linked to cancers and is framed for treatment of BAF-related disorders.
Viral infection, where BAF-related disorders are framed to include antiviral activities.
Cell-based SYO1 BRD9-NanoLuc degradation assay establishing BRD9 degradation potency and IC50 categories.
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