Compounds and methods for the enhanced degradation of targeted proteins
Inventors
Crew, Andrew P. • Crews, Craig M. • Chen, Xin • Dong, Hanqing • Ferraro, Caterina • Qian, Yimin • Siu, Kam • Wang, Jing • Jin, Meizhong • Berlin, Michael • Zimmermann, Kurt • Snyder, Lawrence
Assignees
Yale University • Arvinas Operations Inc
Publication Number
US-12264157-B2
Publication Date
2025-04-01
Expiration Date
2036-03-18
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Abstract
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
Core Innovation
The invention is directed to bifunctional compounds, which act as modulators of targeted ubiquitination by recruiting targeted proteins to E3 ubiquitin ligases, such as the von Hippel-Lindau (VHL) E3 ubiquitin ligase. These compounds comprise a VHL ligand binding to the ubiquitin ligase and a distinct moiety that binds a target protein, positioning the target protein in proximity to the ubiquitin ligase to promote its ubiquitination and subsequent degradation. In particular, these small-molecule, non-peptide-based compounds, referred to as proteolysis targeting chimeras or PROTACs, enable the selective degradation and inhibition of proteins of interest.
The technical problem addressed originates from the challenge in precisely modulating the degradation of specific proteins using conventional therapies. Current methods often lack substrate specificity and may present difficulties in targeting protein-protein interactions with small molecules. The invention identifies the need for effective therapeutics that exploit the specificity of E3 ubiquitin ligases, such as VHL, to degrade disease-related proteins, providing improved pharmacological interventions over general proteasome inhibitors or traditional small molecule drugs.
This patent provides detailed compositions and synthetic methods for a range of PROTACs based on chemical structures that link E3 ubiquitin ligase binding moieties (such as VHL ligands) to protein targeting moieties (PTMs) via various chemical linkers. These bifunctional molecules are designed to ensure the efficient and selective degradation of targeted polypeptides, offering broad applicability in both diagnostic and therapeutic contexts, as well as enabling the construction of chemical libraries for drug discovery.
Claims Coverage
The patent claims focus on the inventive features of bifunctional compounds, pharmaceutical compositions, and methods for treating prostate cancer using such compounds.
Bifunctional compound facilitating proximity-based ubiquitination
A compound comprising: - A structure that includes: - A ubiquitin ligase-binding moiety (ULM), capable of binding an E3 ubiquitin ligase such as VHL. - A protein targeting moiety (PTM), capable of binding to a target protein. - A linker (L) connecting the ULM and PTM, which can be a bond or a chemical linker as described. - The compound is defined by precise chemical groups and substituents (e.g., E, G, J, R7, o, R15, M, R11, R10, as detailed in the claims and description). - Embodiments specify ULM and PTM structures, as well as variations in substituents and linkers. - Examples include compounds where E is C=O, G is C=J, J is O, R7 is H, o is 0, with specified R15 or M groups.
Pharmaceutical compositions comprising the bifunctional compounds
A pharmaceutical composition comprising: - An effective amount of a compound as defined in the inventive feature above, in combination with a pharmaceutically acceptable carrier, additive, or excipient.
Methods of treating prostate cancer using the bifunctional compounds
A method comprising: - Administering a therapeutically effective amount of a compound as defined above to a subject in need thereof for the treatment of prostate cancer. - The method covers compounds selected from specified patent examples and claims.
The claims provide comprehensive coverage for bifunctional compounds targeting proteins for degradation via E3 ubiquitin ligases, pharmaceutical compositions containing these compounds, and methods for treating prostate cancer by administering such compounds.
Stated Advantages
The invention allows specific and efficient degradation of targeted proteins, offering improved substrate specificity compared to general proteasome inhibitors.
Broad pharmacological applicability is achieved, enabling therapeutic effects by directly degrading disease-modulating proteins.
Provides a mechanism to address 'undruggable' pathological proteins that are not viable targets by traditional approaches.
Compounds can be used to construct chemical libraries, supporting drug discovery and identification of novel protein targets.
Bifunctional compounds demonstrate rapid, specific, and long-lasting degradation of target proteins such as the androgen receptor in relevant cell models.
Documented Applications
Therapeutic treatment of diseases or disorders in which degradation of a targeted protein produces a therapeutic effect, including prostate cancer.
Pharmaceutical compositions for use in treating disease states or conditions modulated through degraded proteins, especially in human patients.
Methods for identifying endogenous proteins in biological systems that bind to protein binding moieties in the compounds.
Use of compound libraries to determine activity and pharmacological value of target proteins upon degradation by ubiquitin ligase.
Treatment of a wide range of diseases listed in the patent, including various cancers, autoimmune diseases, metabolic, neurodegenerative, and infectious diseases.
Screening for drug targets and altering levels of proteins in biological systems for therapeutic benefit.
Compositions for treating cancer, including prostate cancer, by selective degradation of disease-associated proteins.
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