Author: Chamakuri, Srinivas ; Pan, Haichun ; Sharma, Kiran L. ; Li, Jian-Yuan ; Ta, Hai Minh ; Wilkinson, Jennifer ; Tang, Suni ; Monsivais, Diana ; Li, Feng ; Young, Damian W. ; Robers, Matthew B. ; Qin, Xuan ; Vasquez, Yasmin M. ; Hakenjos, John M. ; MacKenzie, Kevin R. ; Bohren, Kurt M. ; Tan, Zhi ; Matzuk, Martin M. ; Sankaran, Banumathi ; Mishina, Yuji ; Jimmidi, Ravikumar ; Liao, Zian ; Kim, Choel ; Palmer, Stephen S.

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non–small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure–activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC 50 : 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.

08 Aug 2024·Journal of Medicinal Chemistry

Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2

Article

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

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