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

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Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-18 , 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}

Affiliation

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

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.

中文翻译：

发现两种针对激活素受体样激酶 1 和 2 的高选择性结构正交化学探针

激活素受体样激酶 1-7 (ALK1-7) 调节 SMAD 独立和 SMAD 依赖性信号通路的复杂网络。 LDN-193189是广泛用于这些过程的功能研究，特别是骨形态发生蛋白 (BMP) 信号传导的抑制剂之一。然而， LDN-193189 的全激酶组选择性不足，使其在细胞靶标验证测定中的使用变得复杂。在此，我们报告了两种化学上不同的高度选择性 ALK1 和 ALK2 抑制剂M4K2234和MU1700及其阴性对照的鉴定和综合表征。我们发现， MU1700和M4K2234通过选择性地抑制 ALK1/2 激酶，有效阻断 BMP 通路，并在小鼠体内表现出良好的体内特性。 MU1700具有高度脑渗透性，并且在脑中显示出非常高的积累。这些高质量的正交化学探针提供了成为广泛使用的 BMP 信号传导体外和体内研究工具所需的选择性。

更新日期：2024-07-18

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