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-11414416-B1
Publication Date
2022-08-16
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 relates to a compound having the structure of Formula I, expressed as A-L-B, where A is connected to L through a bond and B is connected to L through a bond. The compound class includes pharmaceutically acceptable salts. The structural definition includes multiple variable substituent options for A, including R4, R5, R6a, and R6b, and for B, including RA5.
In Formula I, L is defined by a linker architecture expressed as A1-(E1)-(F1)-(F2)-(F3)-(E2)-p-A2, where A1 is a bond between the linker and A and A2 is a bond between B and the linker. E1 and E2 are independently selected from O, S, NRN, optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkylene. Each of F1, F2, and F3 is independently optionally substituted C3-C10 carbocyclylene, optionally substituted C2-10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene.
For A, R4, R5, R6a, and R6b are defined with allowed groups including H, halogen, cyano, optionally substituted alkyl, alkenyl, heteroalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, heteroalkenyl, hydroxy, thiol, and optionally substituted amino, with R6a and R6b optionally combining to form optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl. For B, RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. The disclosure presents this as a defined chemical space of Formula I-derived compounds and pharmaceutically acceptable salts.
Claims Coverage
The consolidated content provides one independent claim defining a Formula I compound class with an A-L-B scaffold and a Formula II linker. The coverage centers on four inventive feature groups: the A-side substituent pattern, the B-side substituent pattern, the linker architecture, and the pharmaceutically acceptable salt option.
Formula I compound scaffold with A-L-B connectivity
A compound having the structure of Formula I, where A and B are connected through a linker L defined by Formula II, with A1 as a bond between the linker and A and A2 as a bond between B and the linker.
A-side substituent constraints
For A, R4, R5, R6a, and R6b are defined by the stated classes, including H, halogen, cyano, and optionally substituted alkyl, alkenyl, heteroalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, heteroalkenyl, hydroxy, thiol, and optionally substituted amino, with R6a and R6b optionally combining to form optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl.
Formula II linker structure
L is defined as A1-(E1)-(F1)-(F2)-(F3)-(E2)-p-A2, with E1 and E2 independently selected from O, S, NRN, optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkylene; RN independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; and F1, F2, and F3 independently selected from optionally substituted C3-C10 carbocyclylene, optionally substituted C2-10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene.
B-side substituent constraint
For B, RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.
Pharmaceutically acceptable salts
The compound class includes pharmaceutically acceptable salts.
The claims are centered on a Formula I A-L-B compound scaffold in which the principal inventive coverage is the defined Formula II linker and the constrained substituent options on A and B. The claim set also includes the option of pharmaceutically acceptable salts.
Stated Advantages
Reported that multiple compounds show <1 μM potency in a BRD9 TR-FRET competition binding assay and that several compounds degrade BRD9 with IC50 <1 μM in a NanoLuc degradation assay.
Used to inhibit and/or reduce BRD9, including inhibiting BRD9 level and/or activity in cells.
Provides pharmaceutical compositions for treating cancer and infection indications, including embodiments involving cancer cells.
Supports treating BAF complex-related disorders and SS18-SSX fusion protein-related disorders.
Supports treating BRD9-related disorders by administering effective amounts of the compounds or salts/compositions.
Describes combination therapy options.
Provides BRD9 depletion and sustained suppression as described for a BRD9 degrader example.
Shows selective growth inhibition in synovial sarcoma cell lines versus non-synovial controls, as described in the provided summary.
Produces downstream effects on cell cycle and apoptosis, as described in the provided summary.
Documented Applications
Biochemical assay for BRD9 inhibition using a TR-FRET competition binding assay, with activity tiers and IC50 thresholds reported.
Cell-based BRD9 degradation measurements using a NanoLuc degradation assay, with IC50 values reported and conclusions about BRD9 degradation potency.
Treating BRD9-related disorders by administering effective amounts of the compounds or pharmaceutically acceptable salts and pharmaceutical compositions.
Inhibiting or reducing BRD9 in cells, including embodiments involving cancer cells.
Treating BAF complex-related disorders.
Treating SS18-SSX fusion protein-related disorders.
Using BRD9 inhibition or reduction in the context of cancer and infection indications, with cancer and virus examples described.
Combination therapy options are described.
Therapeutic framing for BRD9/BAF-related cancer, including adult soft tissue sarcoma context as described (synovial sarcoma growth).
Biological targeting and testing context for BRD9 in synovial sarcoma, including an sgRNA tiling screen implicating BRD9 in synovial sarcoma growth.
BRD9 degrader application described as causing dose- and time-dependent BRD9 depletion and sustained suppression, with downstream cell cycle and apoptosis effects.
Proteomics application described as identifying BRD9 as part of SS18-SSX-containing BAF complexes.
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