Fibrodysplasia ossificans progressiva (FOP, MIM #135100) is a rare genetic 
disorder of heterotopic endochondral ossification, resulting in transformation 
of soft tissue into episodic bone formation. Currently, no effective treatment 
for FOP has been established. The causative heterozygous genetic mutations have 
been identified in either the intracellular glycine-serine-rich (GS) domain or 
kinase domain of ALK2 (Activin-like kinase-2, also known as Activin A receptor 
type I, ACVR1), a type I receptor of bone morphogenetic proteins (BMP). 
Cumulative studies support that these mutations abnormally activate BMP 
signaling in a ligandindependent manner by reducing the ALK2 interaction with 
the negative regulator FKBP12, whereas others argue a ligand-dependent BMP 
signaling activation in FOP. Nevertheless, in either the ligand-independent or 
ligand-dependent model, ALK2 receptor activation is essential for heterotopic 
ossification in FOP. Thus targeting ALK2 likely represents an effective 
treatment for FOP. In this article, we critically review the recent progress on 
therapeutic strategies, with a focus on development of small molecule ALK2 
inhibitors to suppress BMP signaling for FOP treatment.