8UWR

Crystal structure of human ACVR1 (ALK2) kinase in complex with compound 3

8UWR の概要

• エントリーDOI: 10.2210/pdb8uwr/pdb
• 分子名称: Activin receptor type-1, SULFATE ION, cyclopropyl(4-{(8R)-6-[4-(piperazin-1-yl)phenyl]pyrrolo[1,2-b]pyridazin-4-yl}piperazin-1-yl)methanone, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, transferase, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38073.26

構造登録者

Kim, J.L. (登録日: 2023-11-07, 公開日: 2024-11-06)

主引用文献

Davis, A.J.,Brooijmans, N.,Brubaker, J.D.,Stevison, F.,LaBranche, T.P.,Albayya, F.,Fleming, P.,Hodous, B.L.,Kim, J.L.,Kim, S.,Lobbardi, R.,Palmer, M.,Sheets, M.P.,Vassiliadis, J.,Wang, R.,Williams, B.D.,Wilson, D.,Xu, L.,Zhu, X.J.,Bouchard, K.,Hunter, J.W.,Graul, C.,Greenblatt, E.,Hussein, A.,Lyon, M.,Russo, J.,Stewart, R.,Dorsch, M.,Guzi, T.J.,Kadambi, V.,Lengauer, C.,Garner, A.P.
An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.
Sci Transl Med, 16:eabp8334-eabp8334, 2024

PubMed Abstract: Fibrodysplasia 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. 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 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 binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2 with high affinity, inhibiting signaling from ALK2 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 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 mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2 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.

PubMed: 38809966
DOI: 10.1126/scitranslmed.abp8334

実験手法

X-RAY DIFFRACTION (2.04 Å)