Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase.,Journal of Medicinal Chemistry

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Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-17 , DOI: 10.1021/acs.jmedchem.0c01125
Sébastien L Degorce ₁ , Omid Tavana ₂ , Erica Banks ₂ , Claire Crafter ₃ , Lakshmaiah Gingipalli ₁ , David Kouvchinov ₄ , Yumeng Mao ₃ , Fiona Pachl ₄ , Anisha Solanki ₃ , Viia Valge-Archer ₃ , Bin Yang ₁ , Scott D Edmondson ₁

Affiliation

We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective IRAK3 ligands in our compound collection with the required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated with the discovery of PROTAC 23, which we demonstrated to be a potent and selective degrader of IRAK3 after 16 h in THP1 cells. 23 induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.

中文翻译：

发现了选择性降解IRAK3假激酶的靶向蛋白水解的嵌合分子。

我们在科学文献中报告了IRAK3降解子的首次公开。利用我们在鉴定IRAK4抑制剂过程中获得的机会副产品的优势，我们在化合物集合中鉴定了具有现成的，选择性的IRAK3配体，这些配体具有转化为靶向蛋白水解的嵌合体（PROTAC）降解物所需的特性。这项工作以PROTAC 23的发现达到高潮，我们证明了它在THP1细胞中经过16小时后是IRAK3的有效和选择性降解剂。23诱导IRAK3的蛋白酶体依赖性降解，并且需要CRBN和IRAK3结合才能产生活性。我们得出的结论是，PROTAC 23构成了一个出色的体外工具，可用来询问IRAK3的生物学特性。

更新日期：2020-09-24

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