| Autor: |
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. |
| Zdroj: |
MedChemComm; 2024, Vol. 15 Issue: 3 p1066-1071, 6p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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