Compounds and uses thereof
Inventors
Ruppel, Sabine K. • Yang, Zhaoxia • LOWE, Jason T. • Voigt, Johannes H. • Netherton, Matthew
Assignees
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Publication Number
US-11560381-B1
Publication Date
2023-01-24
Expiration Date
Abstract
The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.
Core Innovation
The invention provides a compound having the structure of Formula I, together with pharmaceutically acceptable salts thereof. The Formula I scaffold defines groups A, B, and L with bonds between A and L and between B and L, and includes variable positions E1, E2, and E3 as well as multiple R substituents and indices n and p. The disclosed structures encompass a definable and expandable family of compounds within the same core structural framework.
Within Formula I, E1 and E2 are independently O, S, NRN, or optionally substituted alkylene, alkenylene, alkynylene, polyethylene glycol, or heteroalkylene units, and E3 is optionally substituted alkylene, heteroalkylene, O, S, or NRN. The substituent positions include R4, R5, R6a, R6b, R7, R8, each R9, X2, R10b, R34, R35, each R36, R37, and R39, with options including H, halogen, cyano, hydroxy, thiol, and optionally substituted alkyl, alkenyl, heteroalkyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl groups.
The disclosure also defines F1, F2, and F3 as independently optionally substituted carbocyclylene, heterocyclylene, arylene, or heteroarylene, and includes embodiments in which R6a and R6b together with their attachment carbon atoms form optionally substituted aryl or heteroaryl rings. Dependent refinements specify fixed or narrowed selections such as E1 being —CH2—, E2 being O or NRw, n being 1, p being 1, and F3 being optionally substituted C6-C10 arylene. The provided content also describes BRD9-targeting degrader embodiments in which A is a BRD9 binding moiety, B is a degradation moiety, and L is a linker.
Claims Coverage
The claim coverage centers on a Formula I compound with defined A, B, and L connectivity, n and p indices, E1/E2/E3 linker elements, multiple variable R substituents, and pharmaceutically acceptable salts. In the provided claim set, the inventive coverage is broad across the scaffold and linker architecture, with dependent claims narrowing specific substituent identities and discrete parameter values. The consolidated claim scope presents seven recurring inventive features.
Formula I compound scaffold with defined A, B, and linker connectivity
A compound having the structure of Formula I, where A and B are each bonded to L through defined bond relationships and the compound includes pharmaceutically acceptable salts.
Linker region defined by E1, E2, E3, n, and p
L includes E1, E2, and E3, with E1 and E2 independently selected from O, S, NRN, optionally substituted alkylene, alkenylene, alkynylene, polyethylene glycol, or heteroalkylene, and E3 selected from optionally substituted alkylene, heteroalkylene, O, S, or NRN; n and p are each 0 or 1.
Extensive substituent variability across the scaffold
R4, R5, R6a, R6b, R7, R8, each R9, X2, R10b, R34, R35, R36, R37, and R39 are defined by enumerated substituent classes including H, halogen, cyano, hydroxy, thiol, optionally substituted amino, and optionally substituted alkyl, alkenyl, heteroalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl groups.
R6a and R6b ring-forming option
R6a and R6b, together with the carbon atoms to which each is attached, can combine to form optionally substituted aryl or heteroaryl rings.
Defined F1, F2, and F3 groups
Each of F1, F2, and F3 is independently optionally substituted carbocyclylene, heterocyclylene, arylene, or heteroarylene.
Dependent narrowing of linker and terminal groups
Dependent claims specify E1 as —CH2—, E2 as O or NRw, n as 1, p as 1, and F3 as optionally substituted C6-C10 arylene.
BRD9 binding moiety and degradation moiety embodiment
In the BRD9-targeting degrader embodiments, A is a BRD9 binding moiety, B is a degradation moiety, and L is a linker.
Overall, the claim coverage centers on a broad Formula I scaffold with defined A/B/L connectivity, variable linker elements E1/E2/E3, extensive R-group options, and pharmaceutically acceptable salts. Dependent claims narrow the scope by fixing specific substituents and discrete indices, and the BRD9-targeting embodiment identifies A as a BRD9 binding moiety and B as a degradation moiety.
Stated Advantages
BRD9 depletion reduces the SS18-SSX fusion protein associated with synovial sarcoma.
BRD9 may affect antiviral cellular activity.
Selective growth inhibition in synovial sarcoma contexts is described.
BRD9 depletion at the protein level is described as dose/time dependent for a BRD9 degrader example.
Specific growth inhibition is described for synovial sarcoma versus non-synovial controls.
Inhibiting or reducing BRD9 level/activity in cells.
Treating BAF complex-related disorders.
Treating SS18-SSX fusion protein-related disorders.
Treating BRD9-related disorders.
Treatment includes cancer and viral infection, with cancer types enumerated extensively.
Documented Applications
Treating BRD9-related cancer, particularly synovial/soft tissue sarcoma.
Targeting BRD9/BAF complex modulation, including identification of BRD9 within SS18-SSX-containing BAF complexes.
Using antisense and inhibitory RNA agent approaches within a therapeutic framework for BRD9-related disorders.
Modulating antiviral cellular activity associated with BRD9.
Treating BAF complex-related disorders, including cancer and viral infection.
Treating SS18-SSX fusion protein-related disorders, including cancer and viral infection.
Treating BRD9-related disorders, including cancer and viral infection.
Inhibiting or reducing BRD9 level/activity in cells, as part of the therapeutic methods.
Spectroscopic characterization of disclosed compounds using 1H NMR and LCMS.
BRD9 bromodomain TR-FRET competition binding evaluation.
SYO1 BRD9 NanoLuc degradation assay evaluation.
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