Name: Atebrioz (zilurgisertib) in Fibrodysplasia ossificans progressiva: Mechanism of action
Published: 2026-09-27T12:28:00-04:00

Product information and disease description Product description Product information Pharmacology

Mechanism of action

5 evidence topics · 3 sources

Inhibition of wild-type and R206H-mutant ALK2

“FOP is a progressive disease caused by a monoallelic gain-of-function mutation in the activin A receptor, Type I (ACVR1) gene that codes the ALK2 Type I receptor in the bone morphogenetic protein (BMP) signaling pathway. Patients with FOP have constitutively active ALK2 signaling that causes HO. Zilurgisertib is an oral, and selective inhibitor of both wild-type ALK2 and pathogenic ALK2 (R206H mutation). Target engagement of zilurgisertib inhibits ALK2 mediated signaling and reduces endochondral bone formation.” (opens the prescribing information at this quote)

Kinase selectivity in preclinical characterization

“Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species.” (opens the source at this quote in a new tab)

Biochemical selectivity of zilurgisertib against related BMP and TGFβ type I receptor kinases

Kinase	IC50 (μM)	Selectivity ratio (over ALK2 FOP)
ALK2 FOP (ACVR1-R206H)	“0.019”	“−”
ALK2 wild-type (ACVR1)	“0.021”	“1.1”
ALK1 (ACVRL1)	“0.31”	“16”
ALK3 (BMPR1A)	“0.92”	“48”
ALK6 (BMPR1B)	“3.00”	“158”
ALK5 (TGFBR1)	“5.80”	“305”

“We were especially intrigued by the exquisitely high selectivity over ALK5, as the inhibition of ALK5 mediated TGFβ signaling was associated with severe adverse cardiac findings.” (opens the source at this quote in a new tab)
“The lower observed selectivity over ALK1 and ALK3 is consistent with previous reports highlighting the low differences in protein sequence homology between those BMP receptors.” (opens the source at this quote in a new tab)
“The clinical safety of inhibiting ALK1, ALK3, and ALK6 is still under investigation.” (opens the source at this quote in a new tab)

Kinome-wide selectivity screening for zilurgisertib (compound 15)

“The kinome-wide selectivity of 15 was determined by using the DiscoveRx KINOMEscan platform to measure the binding affinities for approximately 450 kinases at 1 μM, and the results are summarized in the kinome dendrogram shown in Figure 3.” (opens the source at this quote in a new tab)
“The kinases bound most strongly by 15 were ALK2 and ALK6, but ALK6 binding did not translate in any corresponding ALK6 inhibitory activity in the mobility shift assay (see Table 2). Beyond the BMP receptor kinase family, 15 interacted with only 11 kinases (20–50% of control), highlighting its supreme selectivity for ALK2 (also see the Supporting Information).” (opens the source at this quote in a new tab)

Role of ALK2 in bone and iron regulation

“Inhibition of BMP signaling by targeting ALK2 to modulate hepatic hepcidin expression and thereby regulate serum iron levels is proposed as a potential treatment for ACD” (opens the source at this quote in a new tab)