9L04

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK783

This is a non-PDB format compatible entry.

Summary for 9L04

• Entry DOI: 10.2210/pdb9l04/pdb
• Descriptor: Activin receptor type-1, 4-(1-ethyl-3-pyridin-3-yl-pyrazol-4-yl)-~{N}-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]pyrimidin-2-amine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, signaling protein, inhibitor complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35590.58

Authors

Sakai, N.,Mishima-Tsumagari, C.,Shirouzu, M. (deposition date: 2024-12-11, release date: 2025-06-25)

Primary citation

Yang, J.,Pan, H.,Sekimata, K.,Hwang, C.,Kulkarni, A.,Thomas, H.,Lindenau, J.,Duford, T.,Ueharu, H.,Tanaka, A.,Sakai, N.,Shirouzu, M.,Hashizume, Y.,Levi, B.,Koyama, H.,Mishina, Y.
A new BMP type 1 receptor kinase inhibitor for safe and efficient oral treatment to prevent genetically induced heterotopic ossification in mice.
Bone, :117565-117565, 2025

PubMed Abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic heterotopic ossification (HO) disorder that currently lacks a practical and definitive preventative approach. FOP is driven by gain-of-function variants in ACVR1, increasing dysregulated BMP signaling pathway, thus resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of RK783, a small-molecule that inhibit BMP type 1 receptor kinase developed for treating FOP. This compound, the result of a rigorous process that involved screening approximately 140,000 compounds in silico with ligand-based structure followed by inhibitory activity and pharmacokinetics studies, offers a promising new direction in treating FOP. RK783 preferentially suppressed both basal and stimulated BMP-Smad1/5/9 signaling in vitro without affecting the signaling of Smad2/3. In vivo, the efficacy of RK783 was demonstrated using two FOP mice models, a conditional knock-in ACVR1-R206H and a transgenic ACVR1-Q207D mouse model, where oral dosing suppressed infiltration of immune cells and differentiation of fibroblast-adipose progenitor (FAP) cells, thus preventing ectopic cartilage and HO formation in muscles. Optimized dosing revealed that high and frequent treatment within the first couple of days after HO induction is critical to successfully suppress HO by RK738. These data suggest that RK783 can be used as an acute medication to prevent HO in FOP.

PubMed: 40516669
DOI: 10.1016/j.bone.2025.117565

Experimental method

X-RAY DIFFRACTION (2.25 Å)