PFI-7 Chemical probe for GID4, substrate-recognition subunit of the CTLH E3 ubiquitin-protein ligase complex

Pfizer in collaboration with the SGC have developed PFI-7, a potent, cell active chemical probe for the E3 ligase GID4. PFI-7 binds potently to GID4 with K_D = 0.08 μM (SPR) and displaces the known degron¹ peptide in a NanoBRET^TM assay with EC₅₀ = 0.6 μM. PFI-7N is a closely related negative control with K_D = 5 μM (SPR). A co-crystal structure has been deposited.

Chemical probe/control pair

We have further developed a handle PFI-E3H1 and a PEGylated analogue to show that the handle tolerates a substitution. These findings offers opportunities to synthesize proximity-inducing or degrader modalities².