Growth factor signaling pathways are tightly regulated by phosphorylation and 
include many important kinase targets of interest for drug discovery. Small 
molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 
(ACVR1) are needed urgently to treat the progressively debilitating 
musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). 
Dorsomorphin analogues, first identified in zebrafish, remain the only BMP 
inhibitor chemotype reported to date. By screening an assay panel of 250 
recombinant human kinases we identified a highly selective 2-aminopyridine-based 
inhibitor K02288 with in vitro activity against ALK2 at low nanomolar 
concentrations similar to the current lead compound LDN-193189. K02288 
specifically inhibited the BMP-induced Smad pathway without affecting TGF-β 
signaling and induced dorsalization of zebrafish embryos. Comparison of the 
crystal structures of ALK2 with K02288 and LDN-193189 revealed additional 
contacts in the K02288 complex affording improved shape complementarity and 
identified the exposed phenol group for further optimization of 
pharmacokinetics. The discovery of a new chemical series provides an independent 
pharmacological tool to investigate BMP signaling and offers multiple 
opportunities for pre-clinical development.