Author: Gomolková, Regina ; Isaac, Methvin B ; Remeš, Marek ; Robers, Matthew B ; Cros, Julien ; Víchová, Ráchel ; Beňovský, Petr ; Vacek, Ondřej ; Al-Awar, Rima ; Kahounová, Zuzana ; Berger, Benedict-Tilman ; Knapp, Stefan ; Corona, Cesear R ; Vasta, James D ; Souček, Karel ; Ursachi, Vlad-Constantin ; Smil, David ; Wong, Jong Fu ; Němec, Václav ; Tse, Lap Hang ; Wells, Carrow I ; Williams, Eleanor ; Bullock, Alex N ; Krejci, Pavel ; Ensan, Deeba ; Paruch, Kamil ; Fafílek, Bohumil ; Šranková, Eliška ; Böck, Michael C

Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.

29 May 2024·Science Translational Medicine

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva

Article

Author: LaBranche, Timothy P ; Zhu, Xing Julia ; Dorsch, Marion ; Lengauer, Christoph ; Davis, Alison J ; Palmer, Michael ; Stevison, Faith ; Garner, Andrew P ; Stewart, Rachel ; Albayya, Faris ; Vassiliadis, John ; Hodous, Brian L ; Xu, Lan ; Brubaker, Jason D ; Fleming, Paul ; Wang, Ruduan ; Guzi, Timothy J ; Lobbardi, Riadh ; Sheets, Michael P ; Wilson, Douglas ; Hunter, Jeffrey W ; Brooijmans, Natasja ; Williams, Brett D ; Kim, Joseph L ; Kim, Sean ; Bouchard, Keith ; Kadambi, Vivek ; Russo, Joelle ; Graul, Chris ; Hussein, Amira ; Greenblatt, Elliot ; Lyon, Morgan

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 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.

01 Jan 2024·International Journal of Biological Macromolecules

Genome-wide characterization of the TGF-β gene family and their expression in different tissues during tail regeneration in the Schlegel's Japanese gecko Gekko japonicus

Article

Author: Wang, Dan-Yan ; Qu, Yan-Fu ; Liu, Qian ; Li, Peng ; Zhao, Ru-Meng ; Ji, Xiang

The transforming growth factor-β (TGF-β) gene family is unique to animals and is involved in various important processes including tissue regeneration. Here, we identified 52 TGF-β family genes based on genome sequences of the gecko (Gekko japonicus), compared TGF-β genes between G. japonicus and other four reptilian species, and evaluated the expression of 14 randomly selected genes in muscle, kidney, liver, heart, and brain during tail regeneration to investigate whether their expression was tissue-dependent. We detected 23 conserved domains, 13 in the TGF-β ligand subfamily, and 10 in the receptor subfamily. The pattern of higher genetic variation in the ligand subfamily than in the receptor subfamily in vertebrates might result from the precise localization of agonists and antagonists in the cell surface and intracellular compartment. TGF-β genes were unevenly distributed across 15 chromosomes in G. japonicus, presumably resulting from gene losses and gains during evolution. Genes in the TGF-β receptor subfamily (ACVR2A, ACVR2B, ACVR1, BMPR1A, ACVRL1, BMPR2 and TGFBR1) played a vital role in the TGF-β signal pathway. The expression of all 14 randomly selected TGF-β genes was tissue-specific. Our study supports the speculation that some TGF-β family genes are involved in the early stages of tail regeneration.

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