Bone morphogenetic protein (BMP) is a protein essential for normal bone growth and other functions in the body. Gene defects that cause too much BMP activity can lead to two diseases: fibrodysplasia ossificans progressive (FOP) and anemia of inflammation (AI). FOP is a rare, inherited and deadly disease in which muscles and tendons turn to bone, making movement difficult. AI is a more common condition in which too much BMP activity in the liver causes anemia. No completely effective treatments exist for either disease. The investigators are developing a drug that inhibits BMP activity and could be used to treat FOP and AI. This project’s aim is to prepare the drug for testing in humans.
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, excessive BMP signaling has been shown to contribute to the pathophysiology of two distinct diseases. The first of these, FOP, is caused by activating mutations in a gene encoding one of the type I BMP receptors. The second disease, 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 not effective enough and have negative 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.
In 2008, the first small molecule inhibitor of BMP signaling was reported. The compound, dorsomorphin, blocks BMP signaling by inhibiting type I BMP 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 project is to advance the development of LDN-193189 in preparation for clinical testing in patients with FOP and AI. The planned developmental steps are applicable to both diseases, leading to efficient use of resources and increased likelihood that LDN-193189 will find successful clinical application in treating patients with these debilitating diseases.
Brigham and Women’s Hospital, Boston
Paul B. Yu, M.D., Ph.D.
Massachusetts General Hospital (General Hospital Corp.), Boston
Donald B. Bloch, M.D.
Kenneth D. Bloch, M.D.
Gregory D. Cuny, Ph.D.
Randall T. Peterson, Ph.D.
Public Health Impact
Two very different diseases, a rare but fatal bone overgrowth disease and a common form of anemia, share a similar underlying cause: over-activation of signals from BMPs. This project will advance development of a newly discovered drug candidate that blocks BMP signaling and will prepare the compound for testing in patients with these diseases.
Initial toxicology studies indicated that LDN-193189 was not a suitable candidate for further Investigational New Drug (IND)-directed development. The lead collaborators proposed a new collaboration with the Therapeutics for Rare and Neglected Diseases (TRND) program to improve the compound through additional medicinal chemistry. BrIDGs support for this project was concluded and the project transferred to TRND.
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology