Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex

bioRxiv (Cold Spring Harbor Laboratory) Pub Date : 2023-11-14 DOI:10.1101/2023.11.13.566858

Aliakbar Khalili Yazdi, Sumera Perveen, Xiaosheng Song, Aiping Dong, Magdalena Szewczyk, Matthew Calabrese, Agustin Casimiro-Garcia, Chakrapani Subramanyam, Matthew S Dowling, Emel Ficici, Jisun Lee, Justin I Montgomery, Thomas N O'Connell, Grzegorz J Skrzypek, Tuan P Tran, Matthew D Troutman, Feng Wang, Jennifer A Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J Brown, Vijayaratnam Santhakumar, Cheryl Arrowsmith, Masoud Vedadi, Dafydd R Owen

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Abstract

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

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人类E3连接酶c端到LisH (CTLH)降解复合物Gid4亚基的化学工具

我们开发了一种新的化学手柄(PFI-E3H1)和一种化学探针(PFI-7)作为人类E3连接酶CTLH降解复合物的Gid4亚基的配体。通过有效的初始hit-ID活动、基于结构的药物设计(SBDD)和利用辉瑞公司庞大的化合物文库，我们仅通过文件筛选就为这种E3连接酶确定了500 nM的配体。进一步的探索确定了一种载体，可以耐受未来嵌合分子设计中添加的连接体。随后对化学型进行优化，使其与化学探针的Gid4结合亲和力低于100 nM。这些新工具，以及合适的阴性对照也被确定，应该能够对这种复杂的人类E3连接酶大分子组装进行询问。

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bioRxiv (Cold Spring Harbor Laboratory)

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