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Crystal structure of human CLK1 kinase in complex with compound 3
Structural highlights
FunctionCLK1_HUMAN Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.[1] [2] 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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