BMP inhibitors and methods of use thereof
Inventors
Alimardanov, Asaf • Cuny, Gregory D. • Grewal, Gurmit S. • Lee, Arthur • McKew, John C. • Mohedas, Agustin H. • Shen, Min • Xu, Xin • Yu, Paul B.
Assignees
Brigham and Womens Hospital Inc • National Institutes of Health NIH
Publication Number
US-10017516-B2
Publication Date
2018-07-10
Expiration Date
2034-03-13
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention provides small molecule inhibitors of BMP signaling. These compounds 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 may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.
Core Innovation
The invention provides small molecule inhibitors of Bone Morphogenetic Protein (BMP) signaling that modulate cell growth, differentiation, proliferation, and apoptosis. These compounds are useful for treating diseases or conditions associated with BMP signaling, such as inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, and for modulating cellular differentiation and/or proliferation. They also reduce circulating levels of ApoB-100 or LDL and treat or prevent various lipid-related diseases, including hypercholesterolemia, hyperlipoproteinemia, and others associated with defects in lipid metabolism.
BMP signaling is a crucial pathway in diverse cellular processes, mediated via a cascade involving type II and type I receptors phosphorylating SMAD proteins, which regulate gene transcription. Its broad roles encompass embryogenesis, organogenesis, and physiological homeostasis, with abnormal BMP signaling implicated in serious diseases such as primary pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, fibrodysplasia ossificans progressiva, and juvenile polyposis syndrome.
Existing approaches to inhibit BMP signaling, including soluble receptors, endogenous inhibitors, or neutralizing antibodies, face challenges due to the structural diversity and complexity of BMP ligands and receptors, as well as limited specificity and affinity. There exists a need for pharmacologic agents that specifically antagonize BMP signaling pathways for therapeutic or experimental uses. The invention addresses this need by providing structurally defined BMP small molecule inhibitors capable of selectively inhibiting BMP-induced phosphorylation of SMAD1/5/8.
Claims Coverage
The patent includes one independent claim focusing on methods of treating diseases or inhibiting BMP signaling using compounds of Formula I or their pharmaceutically acceptable derivatives. The claims cover therapeutic applications targeting specific diseases and a general method of BMP inhibition.
Method of treating BMP signaling-related diseases with compounds of Formula I
A method for treating diseases or conditions benefiting from BMP signaling inhibition, comprising administering to the subject a compound with the structure of Formula I or its pharmaceutically acceptable salt, ester, or prodrug.
Disease treatment scope
The method targets specific diseases including breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, multiple myeloma, ankylosing spondylitis, fibrodysplasia ossificans progressiva, and anemia.
BMP signaling inhibition method
A method of inhibiting BMP signaling in a subject by administering a compound having the structure of Formula I or its pharmaceutically acceptable salt, ester, or prodrug.
The claims cover methods of using compounds of Formula I to inhibit BMP signaling for therapeutic purposes across multiple diseases, including various cancers, bone disorders, and anemia. They define the use of such compounds and their derivatives for treatment and general BMP inhibition in subjects.
Stated Advantages
The compounds overcome difficulties associated with identified metabolism, providing improved in vivo efficacy, simplified dosage regimens, and ultimately improved patient outcomes.
Selective antagonism of BMP signaling pathways potentially reduces toxicity or side effects compared to non-selective inhibitors.
Ability to modulate BMP signaling with small molecule inhibitors addresses the limitations of current approaches, offering practical therapeutic and experimental applications.
Documented Applications
Treatment of anemia, including iron deficiency and anemia of chronic disease, by inhibiting hepcidin expression and increasing serum iron levels.
Treatment of fibrodysplasia ossificans progressiva and prevention of excessive bone formation related to trauma or inflammation.
Treatment of various cancers including breast carcinoma, prostate carcinoma, renal cell carcinoma, bone and lung metastases, osteosarcoma, and multiple myeloma through BMP signaling inhibition.
Immune modulation to augment inflammatory or immune responses, aiding the clearance of infections and managing autoimmune and inflammatory disorders.
Prevention and treatment of pathologic and ectopic bone formation including ankylosing spondylitis, myositis ossificans traumatica, and vascular or valvular calcification.
Promotion of keratinocyte proliferation, improved epithelialization, treatment of psoriasis, and corneal scarring.
Treatment of systemic and pulmonary hypertension by modulating vascular smooth muscle constriction and BMP-related pathways.
Treatment of ventricular hypertrophy and prevention of congestive heart failure.
Treatment of neurological disorders such as spinal cord injury, neuropathies, multiple sclerosis, dementias, and modulation of memory and learning.
Reduction of atherosclerosis, vascular inflammation, and related cardiovascular disease by modulating BMP signaling.
Treatment of hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and related lipid metabolism disorders, including reduction of circulating ApoB-100 and LDL levels.
Manipulation of stem cell differentiation and proliferation for therapeutic applications, including expansion, maintenance of pluripotency, and lineage specification in vitro and in vivo.
Promotion of cartilage repair and inhibition of cartilage calcification in tissue engineering and regenerative medicine.
Potential use as insecticides selective for arthropod BMP receptors.
Interested in licensing this patent?