Compounds and uses thereof
Inventors
Ruppel, Sabine K. • Yang, Zhaoxia • LOWE, Jason T. • Voigt, Johannes H.
Assignees
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Publication Number
US-11851445-B2
Publication Date
2023-12-26
Expiration Date
Abstract
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
Core Innovation
The disclosure relates to BRD9/BAF-complex-targeting compounds and BRD9 degrader compounds defined by particular chemical structures, including pharmaceutically acceptable salts. The disclosed compound set includes specific compounds identified in Table 1, Compound D1, a TFA salt form, and enantiomeric forms S-D1 and R-D1.
The disclosure addresses BAF complex-related disorders and SS18-SSX fusion protein-related disorders by inhibiting or degrading BRD9. It states that BRD9 depletion leads to SS18-SSX fusion protein depletion in cells, and identifies BRD9 as a component of SS18-SSX-containing BAF complexes.
The patent further describes BRD9 degrader performance characterization in a NanoLuc-based assay using SYO-1 and a NanoLuciferase-BRD9 fusion protein, including enantiomer-dependent potency and stability behavior in biological contexts. The disclosure also includes pharmaceutical compositions comprising these compounds and pharmaceutically acceptable excipients.
Claims Coverage
The independent claims include two claim groups: one directed to a structurally defined BRD9/BAF-complex-targeting compound, including a pharmaceutically acceptable salt, and one directed to a pharmaceutical composition comprising that compound or salt plus a pharmaceutically acceptable excipient. The inventive features are structural definition via specific chemical structure depictions, including named variants for S-D1 and R-D1.
Structurally defined BRD9 degrader compound
A compound having the structure shown in one of the provided chemical structure depictions, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with the structurally defined BRD9 degrader compound and excipient
A pharmaceutical composition comprising a compound having the structure shown in one of the provided chemical structure depictions, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The claim coverage is primarily structural: it defines BRD9 degrader compounds by specific chemical structure depictions, including S-D1 and R-D1 variants through dependent claims, and extends those definitions to pharmaceutical compositions by adding a pharmaceutically acceptable excipient.
Stated Advantages
Treating BAF complex-related disorders.
Treating SS18-SSX fusion protein-related disorders.
BRD9 depletion leads to SS18-SSX fusion protein depletion in cells.
Dose- and time-dependent BRD9 depletion and sustained suppression are described.
Selective growth inhibition in synovial sarcoma cell lines versus non-synovial controls is described.
Documented Applications
Treating BAF complex-related disorders, including cancer.
Treating BAF complex-related disorders, including infection/viral infection.
Treating SS18-SSX fusion protein-related disorders, including synovial sarcoma.
BRD9 degrader performance measured in a SYO-1 NanoLuc assay using a NanoLuciferase-BRD9 fusion protein, including reported IC50 values.
Cell and in vivo BRD9 degradation and tumor growth inhibition in a synovial sarcoma tumor model.
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