Simon C. C. Lucas*, Alexander G. Milbradt, Jason Breed, Erwin De Genst, Anne Jackson, Alisa Solovyeva, Bryony Ackroyd, Matthias R. Bauer, Juntai Liu, David Longmire, Dušan Petrović, Emma L. Rivers, Christopher Stubbs, Poppy Winlow, Sana Bazzaz, Paige Dickson, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher D. Hupp, Rachael Jetson, Anthony D. Keefe, Katherine Nugai, John T. S. Yeoman, Ying Zhang, Xian Feng, Dequan Yu and Christopher Phillips,
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引用次数: 0
摘要
STIP1同源性和U-box containing protein 1 (STUB1)，也被称为Hsc70相互作用蛋白（CHIP）的c端，是一种E3连接酶，在通过Hsc70去除错误折叠蛋白的过程中起着至关重要的作用。对CHIP进行DEL筛选以鉴定小分子结合物。通过生物化学和生物物理技术，包括二维核磁共振，确定了两个命中点。x射线晶体结构显示了与肽结合位点的结合。基于片段的解构表明，hit 2是一个合适的优化起点。在优化过程中，从阵列命中的一个意外重排的恶二唑导致了酰胺载体的探索。这导致了化合物5的发现，这是迄今为止确定的CHIP最有效的小分子配体，也是进一步优化成工具分子或PROTAC弹头的合适起点。
Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP from a DNA-Encoded Library Screen
STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
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