Oligonucleotide-based proteolysis targeting chimera
Inventors
Kortylewski, Marcin • SWIDERSKI, Piotr Marek • Rosen, Steven
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12404509-B2
Publication Date
2025-09-02
Expiration Date
Abstract
Compounds and pharmaceutical compositions useful to treat cancer (e.g., lymphoma), neurodegenerative diseases, and autoimmune disorders include (1) a first nucleic acid sequence capable of binding to a transcription factor, for example, a signal transducer and activator of transcription (STAT) factor, such as STAT3, (2) a second nucleic acid sequence capable of binding a Toll-like receptor protein, for example, a CpG oligodeoxynucleotide, and (3) a ubiquitin ligase binding compound capable of binding a ubiquitin ligase protein, for example, a compound that is capable of binding a cereblon protein, such as lenalidomide, pomalidomide, or thalidomide.
Core Innovation
The invention relates to covalently linked nucleic-acidubiquitin-ligase-binding-compound conjugates. The nucleic acid includes a transcription factor binding site and a Toll-like receptor binding nucleic acid, and the ubiquitin ligase binding compound is capable of binding cereblon. The disclosure presents linker and spacer architectures, including multi-segment linker arrangements and covalent bonding through a linker.
Representative embodiments include a signal transducer and activator of transcription 3 (STAT3) binding nucleic acid and a Class A, Class B, or Class C CpG oligodeoxynucleotide. The STAT3 binding nucleic acid may comprise a first STAT3 binding nucleic acid sequence and a second STAT3 binding nucleic acid sequence connected through a spacer, and the spacer is described as substituted or unsubstituted polyglycol, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.
The nucleic-acid component is further defined by sequence identity to specified SEQ ID NOs, with at least 90% sequence identity and related sequence-identity ranges described in the disclosure. The ubiquitin ligase binding compound includes cereblon-binding moieties such as lenalidomide, pomalidomide, thalidomide, and phthalimide-based monovalent ligase binders. The document also states that the conjugates are presented in pharmaceutical composition and therapeutic method contexts.
Claims Coverage
The independent claims cover covalently linked nucleic-acidubiquitin ligase binding compound constructs, including sequence-identity-defined nucleic acids, STAT3-binding nucleic acids, Class A/B/C CpG oligodeoxynucleotides, and cereblon-binding ubiquitin ligase compounds. Across the independent claims, the main inventive features are the nucleic acid selection or structure, the ubiquitin ligase binding compound, and the defined linker or spacer architecture.
Nucleic acid covalently bonded to ubiquitin ligase binding compound
A compound comprising a nucleic acid having at least 90% sequence identity to a nucleic acid selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:7, and SEQ ID NO:8, and one or more ubiquitin ligase binding compounds, wherein the nucleic acid is covalently bonded to the one or more ubiquitin ligase binding compounds.
STAT3 binding nucleic acid, CpG oligodeoxynucleotide, and cereblon-binding ubiquitin ligase through a linker
A compound comprising a signal transducer and activator of transcription 3 (STAT3) binding nucleic acid sequence, a second nucleic acid sequence selected from a Class A CpG oligodeoxynucleotide, a Class B CpG oligodeoxynucleotide, or a Class C CpG oligodeoxynucleotide, and a ubiquitin ligase binding compound capable of binding a cereblon protein, wherein the ubiquitin ligase binding compound is covalently bound to the nucleic acid through a linker.
STAT3 binding nucleic acid with first and second STAT3 binding sequences connected through a spacer
A compound comprising a STAT3 binding nucleic acid sequence comprising a first STAT3 binding nucleic acid sequence and a second STAT3 binding nucleic acid sequence connected through a spacer, wherein the spacer is substituted or unsubstituted polyglycol, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; a second nucleic acid sequence selected from a Class A CpG oligodeoxynucleotide, a Class B CpG oligodeoxynucleotide, or a Class C CpG oligodeoxynucleotide; and a ubiquitin ligase binding compound capable of binding a cereblon protein, wherein the ubiquitin ligase binding compound is covalently bound to the nucleic acid through a linker.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the claimed compound.
Lymphoma treatment by administering the compound
A method for treating lymphoma in a patient by administering a therapeutically effective amount of the claimed compound.
The claims collectively cover covalently linked nucleic-acid constructs with cereblon-binding ubiquitin ligase compounds, including sequence-identity-defined nucleic acids and STAT3/CpG embodiments linked through specified linker or spacer structures. The coverage also includes pharmaceutical compositions and lymphoma treatment.
Stated Advantages
STAT3 degradation is enhanced in lymphoma cells by a specific CSI-2B thalidomide conjugate.
STAT3 degradation in primary splenocytes and tumor cell selectivity is shown.
Documented Applications
Treating lymphoma in a patient by administering a therapeutically effective amount of the compound.
Pharmaceutical composition use in cancer, including lymphoma, autoimmune disorders, neurodegenerative and viral diseases.
Interested in licensing this patent?