Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor

The
bone morphogenetic protein (BMP) signaling pathway has essential
functions in development, homeostasis, and the normal and pathophysiologic
remodeling of tissues. Small molecule inhibitors of the BMP receptor
kinase family have been useful for probing physiologic functions of
BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here
we describe the development of a selective and potent inhibitor of
the BMP type I receptor kinases, LDN-212854, which in contrast to
previously described BMP receptor kinase inhibitors exhibits nearly
4 orders of selectivity for BMP versus the closely
related TGF-β and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to
other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation
of ALK2-mediated signaling, transcriptional activity, and function.
LDN-212854 potently inhibits heterotopic ossification in an inducible
transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva.
These findings represent a significant step toward developing selective
inhibitors targeting individual members of the highly homologous BMP
type I receptor family. Such inhibitors would provide greater resolution
as probes of physiologic function and improved selectivity against
therapeutic targets.