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Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2\n
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SYSNO ASEP 0602077 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2
Author(s) Němec, V. (CZ)
Remeš, M. (CZ)
Beňovský, P. (CZ)
Bock, M. C. (CZ)
Šranková, E. (CZ)
Fu Wong, J. (GB)
Cros, J. (GB)
Williams, E. (GB)
Hang Tse, L. (GB)
Smil, D. (CA)
Ensan, D. (CA)
Isaac, M. B. (CA)
Al-Awar, R. (CA)
Gomolková, Regina (UZFG-Y)
Ursachi, V. (CZ)
Fafílek, Bohumil (UZFG-Y) ORCID
Kahounová, Zuzana (BFU-R) ORCID
Víchová, Ráchel (BFU-R)
Vacek, Ondřej (BFU-R) ORCID
Berger, B.T. (DE)
Wells, C. I. (US)
Corona, C. R. (US)
Vasta, J. D. (US)
Roberts, M. B. (US)
Krejčí, Pavel (UZFG-Y) ORCID
Souček, Karel (BFU-R) RID, ORCID
Bullock, A. N. (GB)Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 67, č. 15 (2024), s. 12632-12659Number of pages 28 s. Publication form Print - P Language eng - English Country US - United States Keywords activin receptor-like kinases 1 and 2 ; protein kinases OECD category Biochemistry and molecular biology R&D Projects LM2023052 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) NW24-08-00280 GA MZd - Ministry of Health (MZ) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UZFG-Y - RVO:67985904 ; BFU-R - RVO:68081707 UT WOS 001272807700001 EID SCOPUS 85198966327 DOI https://doi.org/10.1021/acs.jmedchem.4c00629 Annotation 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. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2025 Electronic address https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00629
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