Bifunctional small molecules to target the selective degradation of circulating proteins
Inventors
Spiegel, David • Caianiello, David • ZHANG, Mengwen
Assignees
Publication Number
US-12364766-B2
Publication Date
2025-07-22
Expiration Date
2039-04-08
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Abstract
The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcγRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.
Core Innovation
The invention discloses bifunctional small molecules comprising a circulating protein binding moiety (CPBM) linked via a linker to a cellular receptor binding moiety (CRBM), which targets membrane receptors on degrading cells such as hepatocytes. The CRBM may specifically bind to the asialoglycoprotein receptor (ASGPR) of hepatocytes or other receptors on degrading cells like LRP1, LDLR, FcγRI, FcRN, Transferrin, or Macrophage Scavenger receptors. These bifunctional molecules form a complex with disease-associated circulating proteins and facilitate their selective internalization and degradation within hepatocytes or macrophages, thereby removing these proteins from circulation.
The problem addressed by the invention arises from various diseases linked to elevated levels of circulating proteins, such as pro-inflammatory cytokines that contribute to autoimmune and inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and certain cancers. Existing therapies, mainly antibody-based inhibitors, have significant drawbacks including large molecular weight, immunogenicity, high cost, short shelf life, and poor oral bioavailability. Hence, there is a strong need for novel, cost-effective, and efficient methods to selectively degrade circulating protein targets.
The invention presents a small molecule strategy that overcomes limitations of traditional antibody-based therapies by combining selective binding to disease-related circulating proteins and directing their targeted delivery to degradative cellular receptors through a covalently linked CRBM. This approach enables endocytosis and lysosomal degradation of the circulating proteins, potentially providing enhanced therapeutic efficacy by eliminating disease-mediating proteins rather than merely inhibiting their activity. Furthermore, the design is versatile, allowing different protein targets to be addressed by altering the CPBM, facilitating treatment of multiple diseases with similar constructs.
Claims Coverage
The patent claims include one independent compound claim and an independent method claim, describing structural features and therapeutic applications. The claims focus on the bifunctional small molecules' structure and their usage in treating diseases related to circulating protein degradation.
Bifunctional compound structure comprising CPBM and CRBM connected by a linker and optional connector
A compound structure containing a circulating protein binding moiety (CPBM) linked covalently through a chemical linker group and optionally a connector (CON) to a cellular receptor binding moiety (CRBM), which binds to receptors on degrading cells such as hepatocytes, enabling selective binding and degradation of circulating proteins.
Pharmaceutical composition containing the bifunctional compounds
Pharmaceutical compositions comprising a therapeutically effective amount of the bifunctional compound together with pharmaceutically acceptable carriers or excipients.
Method of treating or removing excess tumor necrosis factor alpha (TNF-alpha) in subjects
A method of administering a therapeutically effective amount of a compound having the bifunctional structure for selective removal of excess circulating TNF-alpha proteins to treat diseases like rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, and juvenile rheumatoid arthritis.
Combination therapy with additional bioactive agents
The method optionally includes co-administration of at least one additional bioactive agent selected from a large group of anticancer, anti-inflammatory, and immunomodulatory agents, administered concurrently, consecutively, or co-formulated with the bifunctional compound.
Wide range of administration routes and dosage forms
Administration of the bifunctional compound by various routes including oral, inhalation, topical, rectal, nasal, buccal, vaginal, implanted reservoir, and parenteral (e.g., intravenous, subcutaneous, intramuscular) with therapeutically effective amounts ranging typically from about 0.01 to 200 mg/kg.
The independent claims cover bifunctional compounds designed for selective degradation of circulating proteins, pharmaceutical compositions thereof, and their therapeutic use in treating diseases associated with these proteins. The claims also include combined administration with other bioactive agents and various administration routes, emphasizing the compounds' versatility and utility in disease treatment.
Stated Advantages
The bifunctional small molecules combine the specificity and affinity of antibody-based therapies while overcoming issues related to antibody high molecular weight, immunogenicity, cost, short shelf life, and oral bioavailability.
The small molecule approach enables selective binding and degradation of circulating proteins inside hepatocytes or macrophages, potentially leading to more lasting therapeutic effects by eliminating proteins rather than merely inhibiting them.
The composition is more cost-effective and easier to manufacture in large quantities than antibody-based therapies, addressing high demand and cost burdens associated with current treatments.
The modular design allows targeting of various disease-related proteins by simply changing the CPBM, thus providing versatility and broad applicability to multiple diseases.
Documented Applications
Treatment of diseases mediated by elevated circulating proteins, including autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
Treatment of inflammatory diseases including atherosclerosis, heart disease, stroke, and Alzheimer's disease.
Treatment of cancer including leukemia, metastatic cancer, recurrent cancer, and cancers resistant to existing therapies.
Use in removing excess circulating tumor necrosis factor alpha (TNF-alpha) protein to treat diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, and juvenile rheumatoid arthritis.
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