Materials and methods for suppressing and/or treating bone related diseases and symptoms
Inventors
Bellido, Teresita M. • Roodman, G. David • Delgado-Calle, Jesus • Boeckman, Robert K. • Ebetino, Frank H.
Assignees
United States, Represented By Department Of Veteranas Affairs AS • Indiana University Research and Technology Corp • University of Rochester • US Department of Veterans Affairs
Publication Number
US-11672811-B2
Publication Date
2023-06-13
Expiration Date
2038-08-02
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Abstract
Various aspects and embodiments disclosed herein relate generally to the modelling, treatment, reducing resistance to the treatment, prevention, and diagnosis of diseases/symptoms induced by multiple myeloma. Embodiments include methods of treating a bone related disease, comprising the steps of: administering to a subject at least one therapeutically effective dose of a compound disclosed herein.
Core Innovation
The invention relates to compositions and methods for the modeling, treatment, reducing resistance to treatment, prevention, and diagnosis of diseases and symptoms induced by multiple myeloma and other bone-related diseases. This includes methods of treating bone-related diseases by administering a therapeutically effective dose of compounds that comprise a gamma-secretase inhibitor linked to a bone-targeting molecule.
Multiple myeloma is characterized by an abnormal expansion of monoclonal plasma cells in the bone marrow and osteolytic lesions that cause severe bone pain and fractures. The disease exhibits increased bone resorption alongside long-term suppression of bone formation, with the bone marrow microenvironment contributing significantly to tumor growth and bone destruction. Current Notch signaling inhibitors, such as gamma-secretase inhibitors, limit myeloma cell growth and osteoclast differentiation but cause severe side effects, including gastrointestinal toxicity and skin disorders, limiting their clinical use.
This invention addresses the need for novel therapeutic agents that target Notch signaling more selectively within bone tissue to reduce side effects. The disclosed compounds are conjugates of a gamma-secretase inhibitor with a bone-targeting molecule, typically a biphosphonate, connected via a cleavable linker. These conjugates are designed to localize to bone where the linker is cleaved under acidic conditions near osteoclasts, releasing the active inhibitor specifically at the site of bone resorption. This approach inhibits Notch signaling and osteoclast activity selectively within bone while sparing other tissues, thus reducing systemic toxicity.
Claims Coverage
The patent contains multiple independent claims describing novel compounds and their stereoisomers, with inventive features covering chemical structure, specificity, and methods of treatment.
Compound comprising a gamma-secretase inhibitor linked to a bone-targeting molecule
A compound comprising A-Y-B, where A is at least one agent that reduces and/or inhibits gamma-secretase activity, B is at least one bone-targeting molecule (such as biphosphonates optionally substituted with OH, halogen, CH3, NH2, N-alkyl, or N-dialkyl), and Y is a linker joining A and B, optionally cleavable in an acidic bone microenvironment.
Compound comprising one or more specified stereoisomers
A compound comprising one or more stereoisomers characterized by the formula with defined ranges for substituents n, m, and X, representing chemical groups linked structurally to the inhibitor and bone-targeting moieties.
Specific stereoisomeric configurations and chemical formulae
Compounds including specific stereoisomer forms exemplified by chemical structures that show particular substituents and configurations enhancing bone targeting and gamma-secretase inhibition.
The claims cover novel chemical compounds that combine gamma-secretase inhibitors with a bone-targeting moiety via a linker, specifically designed to release the inhibitor in bone tissue, as well as stereoisomeric variations of such compounds. The claims further encompass methods of using these compounds to treat bone-related diseases with enhanced efficacy and reduced systemic side effects.
Stated Advantages
Bone-specific inhibition of Notch signaling reduces osteoclast formation without affecting osteoblast activity.
Reduced systemic toxicity compared to unconjugated gamma-secretase inhibitors, particularly avoiding gastrointestinal and skin side effects.
The compounds increase bone mineral density and decrease markers of bone resorption effectively.
The combination with parathyroid hormone administration demonstrates synergistic enhancement of bone mass gains while reducing bone resorption.
Documented Applications
Treatment of bone-related diseases such as multiple myeloma, osteopenia, osteoporosis, rheumatoid arthritis, and various cancers involving bone.
Reducing growth of myeloma cells and osteoclast differentiation to improve skeletal disease conditions.
Use in methods combining the compound with parathyroid hormone and/or proteasome inhibitors to improve bone health and treat bone-related diseases.
Formulations for administration via multiple routes including oral, parenteral, subcutaneous, intramuscular, and mucosal delivery.
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