Compounds 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-12391686-B2
Publication Date
2025-08-19
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 provides a compound having the structure of Formula II, wherein L is a linker having the structure of Formula IV and B is a degradation moiety having the structure of Formula A. The compound is defined by A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2, with A1 being a bond between the linker and A and A2 being a bond between B and the linker, and with f, g, h, i, j, and k each independently 0 or 1.
In the linker portion, B1, B2, B3, and B4 are independently optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, or NRN, and each RN is independently H or optionally substituted alkyl, alkenyl, alkynyl, heterocyclyl, aryl, or heteroalkyl. C1 and C2 are independently carbonyl, thiocarbonyl, sulphonyl, or phosphoryl, and D is optionally substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C2-C10 polyethylene glycol, or C1-10 heteroalkyl, or a chemical bond.
The degradation moiety B is defined by Formula A and includes Y1, RA5, RA6, RA7, and RA8, with RA5 being H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and with RA6 and RA7 independently H or optionally substituted C1-C6 alkyl. RA6 and RA7 together with the carbon atom to which each is bound can form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl, and Formula A further includes Formula III with R1, Z1, R2, X1, X2, R7, R7′, X3, X4, G″, and G′, together with pharmaceutically acceptable salts.
Claims Coverage
The consolidated material identifies one independent claim, clm-00001, directed to a Formula II compound with a Formula IV linker and a Formula A degradation moiety. The inventive scope centers on the A1-(B1)f-(C1)g-(B2)h-(D)-(B3)i-(C2)j-(B4)k-A2 connectivity, the variable linker segments and optional bond presence, and the defined substituent classes for the linker and degradation moiety.
Formula II compound with Formula IV linker and Formula A degradation moiety
A compound having the structure of Formula II, wherein L is a linker having the structure of Formula IV and B is a degradation moiety having the structure of Formula A, with A1 being a bond between the linker and A and A2 being a bond between B and the linker.
Variable linker substituents and optional connection pattern
B1, B2, B3, and B4 are independently optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, O, S, S(O)2, or NRN; each of f, g, h, i, j, and k is independently 0 or 1; C1 and C2 are independently carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and D is optionally substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C2-C10 polyethylene glycol, C1-10 heteroalkyl, or a chemical bond.
Degradation moiety Formula A with Formula III variable scaffold
B is a degradation moiety having the structure of Formula A, including Y1, RA5, RA6, RA7, and RA8, where RA6 and RA7 can combine with the carbon atom to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl, and Formula A further includes Formula III with variables R1, Z1, R2, X1, X2, R7, R7′, X3, X4, G″, and G′, including pharmaceutically acceptable salts.
The independent claim covers a Formula II compound class built from a Formula IV linker and a Formula A degradation moiety, with broadly selectable linker segments, optional bond presence, ring-forming options, and pharmaceutically acceptable salts.
Stated Advantages
Selectively inhibits growth of synovial sarcoma cell lines.
Does not inhibit growth of non-synovial control cancer lines.
Reduces S-phase cells and increases early and late apoptosis in SYO1 cells.
Identifies BRD9 as an interacting component in SS18-SSX1-containing BAF complexes.
Inhibiting/depleting BRD9 level and/or activity.
Treating BRD9-related, BAF-complex-related, and SS18-SSX fusion-related disorders.
Inhibiting cell growth effects.
Documented Applications
Use of BRD9-targeting compounds to selectively inhibit growth of synovial sarcoma cell lines.
Treatment of synovial sarcoma in a subject by administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.
A method for treating synovial sarcoma in a subject by administering an effective amount of a compound of the claimed Formula II or a pharmaceutically acceptable salt thereof.
Therapeutic use for inhibiting/depleting BRD9 and treating BRD9-related, BAF-complex-related, and SS18-SSX fusion-related disorders.
Example indications include cancer and viral/infection indications.
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