Development of Bone Morphogenetic Protein Inhibitors to Treat Blood and Bone Disorders
Bone morphogenetic protein (BMP) signals have been known for decades to play essential roles in normal embryonic development. More recently, it has been recognized that BMP signals also play important roles in adults. In fact, within the past three years, excessive BMP signaling has been shown to contribute to the pathophysiology of two distinct diseases. The first of these, fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which soft tissues (e.g., muscles and tendons) turn to bone, leading to immobility and death. FOP is caused by activating mutations in a gene encoding one of the type I BMP receptors. The second disease, anemia of inflammation (AI), is a common condition in which chronic inflammation leads to anemia through excess BMP signaling in the liver. There are no available treatments for FOP patients, and therapies for AI are incompletely effective and have important side-effects. As the significance of BMP signaling for these two diseases has become known, development of BMP signaling inhibitors has emerged as an important goal.
Recently, the first small molecule inhibitor of BMP signaling was reported. The compound, dorsomorphin, blocks BMP signaling by inhibiting BMP type I receptors. Through medicinal chemistry optimization, dorsomorphin derivatives were developed, including LDN-193189, a compound with much greater potency (~5 nM in cells) and specificity than the parent compound. LDN-193189 is well tolerated in mice, has low toxicity and is orally available. Most importantly, LDN-193189 has proven to be efficacious in treating FOP and AI in mouse models of these diseases.
The overall objective of this research proposal is to advance the development of LDN-193189 in preparation for clinical testing in patients with FOP and AI. The planned developmental steps will be applicable to both proposed disease indications, leading to efficient use of resources and increased likelihood that LDN-193189 will find successful clinical application in treating patients with debilitating diseases.
Massachusetts General Hospital (General Hospital Corp.)
Kenneth D. Bloch, M.D.
Gregory D. Cuny, Ph.D.
Randal T. Peterson, Ph.D.
Paul B. Yu, M.D., Ph.D.
Public Health Impact
It recently has been discovered that two very different diseases, a rare but fatal bone overgrowth disease called fibrodysplasia ossificans progressiva and a common form of anemia called anemia of inflammation, share a similar underlying cause: hyperactivation of signals from bone morphogenetic proteins (BMPs). This application proposes to advance development of a newly discovered drug candidate that blocks BMP signaling and to prepare the compound for testing in patients with these diseases.
Approved studies are ongoing.
- Synthesis of GMP and non-GMP material
- Formulation development
- PK/ADME studies
- IND-directed toxicology