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

Yazdi, A. K.; Perveen, S.; Song, X.; Dong, A.; Szewczyk, M.; Calabrese, M.; Casimiro-Garcia, A.; Subramanyam, C.; Dowling, M. S.; Ficici, E.; Lee, J.; Montgomery, J. I.; O'Connell, T. N.; Skrzypek, G. J.; Tran, T. P.; Troutman, M. D.; Wang, F.; Young, J. A.; Min, J.; Barsyte-Lovejoy, D.; Brown, P. J.; Santhakumar, V.; Arrowsmith, C.; Vedadi, M.; Owen, D. R.

doi:10.1101/2023.11.13.566858

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bioRxiv · 10.1101/2023.11.13.566858

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

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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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Yazdi, A. K., Perveen, S., Song, X., Dong, A., Szewczyk, M., Calabrese, M., Casimiro-Garcia, A., Subramanyam, C., Dowling, M. S., Ficici, E., Lee, J., Montgomery, J. I., O'Connell, T. N., Skrzypek, G. J., Tran, T. P., Troutman, M. D., Wang, F., Young, J. A., Min, J., Barsyte-Lovejoy, D., Brown, P. J., Santhakumar, V., Arrowsmith, C., Vedadi, M., Owen, D. R.. 2023-11-14. Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex. https://doi.org/10.1101/2023.11.13.566858

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