Haag Adrian, Němec Václav, Janovská Pavlína, Bartošíková Jana, Adhikari Bikash, Müller Juliane, Schwalm Martin P, Čada Štěpán, Ohmayer Uli, Daub Henrik, Kim Yeojin, Born Florian, Wolf Elmar, Bryja Vítězslav, Knapp Stefan
Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
J Med Chem. 2025 Jan 9;68(1):506-530. doi: 10.1021/acs.jmedchem.4c02201. Epub 2024 Dec 27.
Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 () targeting CK1δ and CK1ε with excellent selectivity over the highly related CK1α isoform. The developed PROTAC, AH078 () selectively degraded CK1δ and CK1ε with a DC of 200 nM. Characterization of AH078 () revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 () represents a versatile chemical tool to study CK1δ and CK1ε function in cellular systems.
酪蛋白激酶1（CK1）家族成员已成为细胞信号传导的关键调节因子和潜在的药物靶点。对7种人类同工型进行功能注释将受益于同工型选择性抑制剂，从而能够研究这些酶在正常生理和疾病发病机制中的作用。然而，由于催化结构域内存在显著的序列同源性，使用传统小分子很难实现同工型选择性。在此，我们采用了一种PROTAC（蛋白酶靶向嵌合体）方法来开发一种高度选择性的降解剂AH078（），该降解剂靶向CK1δ和CK1ε，对高度相关的CK1α同工型具有出色的选择性。所开发的PROTAC，即AH078（），以200 nM的DC选择性降解CK1δ和CK1ε。对AH078（）的表征揭示了一种VHL和泛素依赖性的降解机制。因此，AH078（）是一种在细胞系统中研究CK1δ和CK1ε功能的通用化学工具。
