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Crystal structure of human ACVR1 (ALK2) kinase in complex with compound 3
Structural highlights
DiseaseACVR1_HUMAN Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM:135100. FOP is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification in FOP begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to extra-articular ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible.[1] [2] [3] FunctionACVR1_HUMAN On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). Publication Abstract from PubMedFibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2(R206H). In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway 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 BLU-782 (IPN60130), a small-molecule ALK2(R206H) inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2(R206H) binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2(R206H) with high affinity, inhibiting signaling from ALK2(R206H) and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2(R206H) mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2(R206H) mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2(R206H) mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP. An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.,Davis AJ, Brooijmans N, Brubaker JD, Stevison F, LaBranche TP, Albayya F, Fleming P, Hodous BL, Kim JL, Kim S, Lobbardi R, Palmer M, Sheets MP, Vassiliadis J, Wang R, Williams BD, Wilson D, Xu L, Zhu XJ, Bouchard K, Hunter JW, Graul C, Greenblatt E, Hussein A, Lyon M, Russo J, Stewart R, Dorsch M, Guzi TJ, Kadambi V, Lengauer C, Garner AP Sci Transl Med. 2024 May 29;16(749):eabp8334. doi: 10.1126/scitranslmed.abp8334. , Epub 2024 May 29. PMID:38809966[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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