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

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

  • J Med Chem. 2024 Aug 8;67(15):12632-12659. doi: 10.1021/acs.jmedchem.4c00629.
Václav Němec 1 2,  Marek Remeš 2,  Petr Beňovský 2,  Michael C Böck 2,  Eliška Šranková 2,  Jong Fu Wong 3,  Julien Cros 3,  Eleanor Williams 3,  Lap Hang Tse 3,  David Smil 4,  Deeba Ensan 4,  Methvin B Isaac 4,  Rima Al-Awar 4 5,  Regina Gomolková 6 7,  Vlad-Constantin Ursachi 6 8,  Bohumil Fafílek 6 7 8,  Zuzana Kahounová 9,  Ráchel Víchová 9,  Ondřej Vacek 8 9,  Benedict-Tilman Berger 1,  Carrow I Wells 10,  Cesear R Corona 11,  James D Vasta 11,  Matthew B Robers 11,  Pavel Krejci 6 7 8,  Karel Souček 8 9,  Alex N Bullock 3,  Stefan Knapp 1,  Kamil Paruch 2 7
Affiliations

Affiliations

  • 1 Institute for Pharmaceutical Chemistry, Structural Genomics Consortium, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, Frankfurt am Main, 60438, Germany.
  • 2 Department of Chemistry, Masaryk University, Brno 625 00, Czech Republic.
  • 3 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
  • 4 Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, Ontario M5G 0A3, Canada.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 6 Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic.
  • 7 Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 602 00 Brno, Czech Republic.
  • 8 International Clinical Research Center, St. Anne's University Hospital, 602 00 Brno, Czech Republic.
  • 9 Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 00 Brno Czech Republic.
  • 10 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 11 Promega Corporation, Madison, Wisconsin 53716, United States.
PMID: 39023313 DOI: 10.1021/acs.jmedchem.4c00629
Abstract

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.

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