2024
Němec, Václav; Remeš, Marek; Beňovský, Petr; Böck, Michael C.; Šranková, Eliška; Wong, Jong Fu; Cros, Julien; Williams, Eleanor; Tse, Lap Hang; Smil, David; Ensan, Deeba; Isaac, Methvin B.; Al-Awar, Rima; Gomolková, Regina; Ursachi, Vlad-Constantin; Fafílek, Bohumil; Kahounová, Zuzana; Víchová, Ráchel; Vacek, Ondřej; Berger, Benedict-Tilman; Wells, Carrow I.; Corona, Cesear R.; Vasta, James D.; Robers, Matthew B.; Krejci, Pavel; Souček, Karel; Bullock, Alex N.; Knapp, Stefan; Paruch, Kamil
Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2. Journal Article
In: Journal of medicinal chemistry, vol. 67, no. 15, pp. 12632–12659, 2024, ISSN: 1520-4804 0022-2623, (Place: United States).
Abstract | Links | BibTeX | Tags: *Activin Receptors, Activin Receptors, Animals, Bone Morphogenetic Proteins/metabolism, Drug Discovery, Humans, Mice, Molecular Probes/chemistry, Protein Kinase Inhibitors/pharmacology/chemistry, Pyrazoles/chemistry/pharmacology/chemical synthesis, Signal Transduction/drug effects, Structure-Activity Relationship, Type I/antagonists & inhibitors/metabolism, Type II/metabolism/antagonists & inhibitors
@article{nemec_discovery_2024,
title = {Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2.},
author = {Václav Němec and Marek Remeš and Petr Beňovský and Michael C. Böck and Eliška Šranková and Jong Fu Wong and Julien Cros and Eleanor Williams and Lap Hang Tse and David Smil and Deeba Ensan and Methvin B. Isaac and Rima Al-Awar and Regina Gomolková and Vlad-Constantin Ursachi and Bohumil Fafílek and Zuzana Kahounová and Ráchel Víchová and Ondřej Vacek and Benedict-Tilman Berger and Carrow I. Wells and Cesear R. Corona and James D. Vasta and Matthew B. Robers and Pavel Krejci and Karel Souček and Alex N. Bullock and Stefan Knapp and Kamil Paruch},
doi = {10.1021/acs.jmedchem.4c00629},
issn = {1520-4804 0022-2623},
year = {2024},
date = {2024-08-01},
journal = {Journal of medicinal chemistry},
volume = {67},
number = {15},
pages = {12632–12659},
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.},
note = {Place: United States},
keywords = {*Activin Receptors, Activin Receptors, Animals, Bone Morphogenetic Proteins/metabolism, Drug Discovery, Humans, Mice, Molecular Probes/chemistry, Protein Kinase Inhibitors/pharmacology/chemistry, Pyrazoles/chemistry/pharmacology/chemical synthesis, Signal Transduction/drug effects, Structure-Activity Relationship, Type I/antagonists & inhibitors/metabolism, Type II/metabolism/antagonists & inhibitors},
pubstate = {published},
tppubtype = {article}
}