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-11654147-B2
Publication Date
2023-05-23
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 present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions are used to modulate cell growth, differentiation, proliferation, and apoptosis. The compounds are useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, bone disorders, Sjögren's syndrome, and diffuse intrinsic pontine glioma (DIPG). The invention includes compounds of Formula I or Formula I-a, pharmaceutically acceptable salts, esters, or prodrugs thereof.
The problem addressed concerns the structural diversity of the BMP and TGF-β superfamily and the complexity of their receptor-ligand interactions, making traditional approaches such as soluble receptors, endogenous inhibitors, or neutralizing antibodies impractical or ineffective for BMP inhibition. Existing endogenous inhibitors have limited specificity, and neutralizing antibodies are limited by the structural diversity of the signaling system. There is thus a need for pharmacologic agents that specifically antagonize BMP signaling pathways for therapeutic or experimental use.
Claims Coverage
The patent contains one independent claim covering compounds of formula (I) and various methods and compositions involving these compounds. The main inventive features concern the chemical structure of the inhibitors and their uses in therapeutic methods.
Chemical structure of BMP signaling inhibitors
A compound of formula (I), or a pharmaceutically acceptable salt thereof, with defined structural moieties including A1, B1, Z1, R1, R2, R3, R4a, R4b, R5, and R6, where each substituent is selected from specified chemical groups such as aryl, heteroaryl, heterocyclyl, alkyl, alkoxy, amino, halo, oxo, and where additional constraints on ring formation and substitution patterns apply.
Pharmaceutical compositions
Pharmaceutical compositions comprising the compounds of formula (I) or salts thereof combined with pharmaceutically acceptable excipients.
Method of treating anemia
Methods for treating anemia including iron deficiency anemia or anemia of inflammation by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Method of treating fibrodysplasia ossificans progressiva (FOP)
Methods for treating subjects with FOP by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The claims cover specifically structured compounds as BMP signaling inhibitors, their pharmaceutical compositions, and their therapeutic applications for treating diseases related to BMP signaling, including anemia and fibrodysplasia ossificans progressiva.
Stated Advantages
The compounds show potent enzymatic and cellular activity, with improved absorption, distribution, metabolism, and excretion properties.
Selective inhibition of ALK2 receptor to minimize toxicity and side effects.
Compounds can be used to effectively inhibit BMP signaling in various disease contexts.
Documented Applications
Treatment or prevention of diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, bone disorders, Sjögren's syndrome, and diffuse intrinsic pontine glioma (DIPG).
Modulation of abnormal bone formation in soft tissue including heterotopic ossification diseases such as fibrodysplasia ossificans progressiva, ankylosing spondylosis, traumatic heterotopic ossification, and burn- or blast-injury associated heterotopic ossification.
Treatment of anemia, including iron deficiency anemia and anemia of chronic disease via hepcidin regulation.
Treatment and prevention of pulmonary hypertension, systemic hypertension, vascular calcification, and atherosclerosis.
Treatment of cancers including breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma.
Treatment of skin diseases, including promotion of keratinocyte proliferation, improved epithelialization, hair growth, psoriasis, and corneal scarring.
Treatment of neurological disorders associated with central nervous system inflammation, spinal cord injury, neuropathy, dementia including Alzheimer's disease, and cognitive function.
Increasing salivary flow and treating Sjögren's syndrome by inhibiting BMP6 expression or activity.
Modulation of stem cell differentiation and expansion both in vitro and in vivo.
Use as insecticides or pest control agents through inhibition of BMP signaling in arthropods.
Ex vivo treatment of cells, tissues, and implantable materials.
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