ALK2 inhibitors and methods for inhibiting BMP signaling
Inventors
Yu, Paul B. • HUANG, Wenwei • Sanderson, Philip Edward • Jiang, Jian-Kang • SHAMIM, Khalida • Zheng, Wei • Huang, Xiuli • Tawa, Gregory • Lee, Arthur • Alimardanov, Asaf • Huang, Junfeng
Assignees
Brigham and Womens Hospital Inc • US Department of Health and Human Services
Publication Number
US-11026947-B2
Publication Date
2021-06-08
Expiration Date
2038-04-26
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Abstract
The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).
Core Innovation
The invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as modulating cellular differentiation and/or proliferation. They may also be used to treat subjects with Sjögren's syndrome or diffuse intrinsic pontine glioma (DIPG).
The compounds of the invention include compounds of Formula I (and Formula I-a), with specific substitutions as disclosed, that inhibit ALK2 and related BMP type I and type II serine/threonine kinase receptors. Methods include administering these compounds to treat or prevent diseases or conditions involving abnormal bone formation in soft tissue, Sjögren's syndrome, DIPG, and other BMP-associated diseases.
The background outlines the complexity and importance of BMP signaling via TGF-β superfamily receptors, specific roles of BMP in development and disease, and the lack of effective pharmacologic agents to specifically antagonize BMP signaling. Existing approaches such as soluble receptors, endogenous inhibitors, and neutralizing antibodies have limited specificity and efficacy due to structural diversity and complexity of ligand-receptor interactions. Thus, there is a need for specific BMP pathway inhibitors.
Claims Coverage
The patent contains one set of independent claims focusing on compounds of Formula I and their pharmaceutical compositions, as well as therapeutic methods using these compounds to treat conditions associated with BMP signaling.
BMP signaling inhibitors of defined compound formula
Compounds of Formula I characterized by specified substituents including A1, B1, Z1, R1-R6 with particular chemical groups or rings, and their pharmaceutically acceptable salts and prodrugs, designed for inhibition of BMP pathway receptors.
Pharmaceutical composition comprising BMP inhibitors
Pharmaceutical compositions comprising one or more compounds of Formula I or pharmaceutically acceptable salts/prodrugs thereof, combined with pharmaceutically acceptable excipients.
Method for treating abnormal bone formation in soft tissue
Methods for treating formation of abnormal bone in soft tissue by administering therapeutically effective amounts of compounds of Formula I, including subjects at risk due to trauma or injury, and heterotopic ossification diseases such as fibrodysplasia ossificans progressiva.
Combination therapies with BMP inhibitors
Methods comprising administering compounds of Formula I in combination with additional agents such as corticosteroids, NSAIDs, anti-inflammatory agents, anti-growth factors, anti-osteogenic or anti-chondrogenic agents, or other immunomodulatory drugs to enhance therapeutic effect.
Inhibition of BMP type I serine-threonine kinase receptors
Methods of inhibiting BMP type I serine-threonine kinase receptors such as ALK2, ALK3, or ALK6 by administering compounds of Formula I to subjects to treat BMP-related disorders.
Treatment of Sjögren's syndrome
Methods for treating Sjögren's syndrome by administering therapeutically effective amounts of BMP6 inhibitors or BMP signaling inhibitors comprising compounds of Formula I.
Treatment of diffuse intrinsic pontine glioma (DIPG)
Methods for treating DIPG by administering therapeutically effective amounts of one or more compounds of Formula I.
Use of compounds for diagnosis and treatment of other BMP-related diseases
Methods for modulating BMP receptor activity and treating diseases involving BMP signaling such as cancers including breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, and inflammatory disorders.
The claims focus on novel compounds of Formula I that inhibit BMP signaling by targeting specific serine-threonine kinase receptors, pharmaceutical compositions containing these compounds, and methods of using these compounds to treat a range of BMP signaling-associated diseases, including heterotopic ossification, Sjögren's syndrome, DIPG, and certain cancers, optionally in combination with other therapeutic agents.
Stated Advantages
The compounds show potent enzymatic and cellular activity and selectivity as ALK2 inhibitors with improved ADME properties, such as decreased susceptibility to aldehyde oxidase metabolism.
Selective inhibition of ALK2 relative to other BMP receptors may reduce toxicity and side effects and allow more effective treatment of diseases caused by aberrant BMP signaling.
The compounds have broad therapeutic potential across multiple diseases associated with BMP signaling, including heterotopic ossification, anemia, cancer, skin diseases, pulmonary hypertension, and Sjögren's syndrome.
Documented Applications
Treatment of diseases or conditions associated with BMP signaling, including heterotopic ossification diseases (acquired heterotopic ossification, fibrodysplasia ossificans progressiva, anklyosing spondylosis, traumatic heterotopic ossification, burn- or blast-injury associated heterotopic ossification, joint replacement surgery associated heterotopic ossification).
Treatment of Sjögren's syndrome by inhibiting BMP6 expression or activity to increase salivary flow.
Treatment of diffuse intrinsic pontine glioma (DIPG).
Treatment of pathological bone formation, vascular calcification, atherosclerosis, anemia, inflammatory disorders, certain cancers including breast and prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, multiple myeloma, pulmonary hypertension, ventricular hypertrophy, skin diseases, neurologic disorders, immune modulation, cartilage defects, and disorders associated with hypercholesterolemia or hyperlipidemia.
Use in stem cell propagation, engraftment, and differentiation in vitro and in vivo.
Use as insecticides or pest control agents by targeting arthropod BMP receptors.
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