Yazdi Aliakbar Khalili, Perveen Sumera, Dong Cheng, Song Xiaosheng, Dong Aiping, Szewczyk Magdalena M, Calabrese Matthew F, Casimiro-Garcia Agustin, Chakrapani Subramanyam, Dowling Matthew S, Ficici Emel, Lee Jisun, Montgomery Justin I, O'Connell Thomas N, Skrzypek Grzegorz J, Tran Tuan P, Troutman Matthew D, Wang Feng, Young Jennifer A, Min Jinrong, Barsyte-Lovejoy Dalia, Brown Peter J, Santhakumar Vijayaratnam, Arrowsmith Cheryl H, Vedadi Masoud, Owen Dafydd R
Structural Genomics Consortium, University of Toronto Toronto ON Canada.
Pfizer Research & Development Groton CT USA.
RSC Med Chem. 2024 Mar 5;15(3):1066-1071. doi: 10.1039/d3md00633f. eCollection 2024 Mar 20.
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.
我们开发了一种新型化学手柄（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。通过高效的初始命中识别活动、基于结构的药物设计（SBDD）以及利用辉瑞庞大的化合物库，我们仅通过文件筛选就为这种E3连接酶确定了一种500 nM的配体。进一步探索确定了一种载体，该载体能够耐受添加连接子以用于未来的嵌合分子设计。随后对化学类型进行了优化，使化学探针与Gid4的结合亲和力达到亚100 nM。这些新型工具，连同同样确定的合适阴性对照，应该能够对这种复杂的人类E3连接酶大分子组装体进行研究。
