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.

Centre for Medicines Discovery Nuffield Department of Medicine University of Oxford Oxford OX3 7FZ U K

Department of Biology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Chemistry Masaryk University Brno 625 00 Czech Republic

Department of Pharmacology and Toxicology University of Toronto Toronto Ontario M5S 1A8 Canada

Drug Discovery Program Ontario Institute for Cancer Research 661 University Avenue Toronto Ontario M5G 0A3 Canada

Institute for Pharmaceutical Chemistry Structural Genomics Consortium Johann Wolfgang Goethe University Max von Laue Strasse 9 Frankfurt am Main 60438 Germany

Institute of Animal Physiology and Genetics of the Czech Academy of Sciences 602 00 Brno Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 612 00 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital 602 00 Brno Czech Republic

Promega Corporation Madison Wisconsin 53716 United States

Structural Genomics Consortium UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina 27599 United States

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Structural Genomics Consortium. M4K2234 Chemical probe for ALK1 and ALK2 protein kinases. https://www.thesgc.org/chemical-probes/m4k2234.

Structural Genomics Consortium. MU1700 Chemical probe for ALK1 and ALK2 protein kinases. https://www.thesgc.org/chemical-probes/mu1700.