New pyrimidinamine scaffold blocks both glutaminyl cyclases and lowers pE-CD47 on cancer cells
- Substrate-mimetic design guided by structure yielded a methylimidazolylethyl-pyrimidinamine series that hits both secretory and Golgi glutaminyl cyclases, which are zinc enzymes.
- The lead, compound 25, strongly stabilised both enzymes, and its co-crystal structure with sQC shows zinc binding plus a hydrogen bond to Gln 304, echoing how the natural substrate is recognised.
- In MDA-MB-231 breast cancer cells it cut pyroglutamylated CD47 at the surface while leaving total CD47 largely unchanged.
- It showed little activity across 14 other metalloenzymes, supporting selectivity.
💡 Points Based on the abstract
An imidazole zinc-binder is the classic QC pharmacophore (PBD150 and the benzimidazole series), so the pyrimidinamine's novelty is mostly in the scaffold and its dual sQC/gQC reach. I'd want isoform potency separated from thermal stabilisation, since a shift is not Ki. Also missing: proof that pE-CD47 loss actually weakens CD47-SIRPα binding or boosts phagocytosis, plus cell permeability and metabolic stability of the imidazole.
📄 Paper · European Journal of Medicinal Chemistry (Elsevier) ↗ Discovery of methylimidazolylethyl-pyrimidinamine derivatives as new glutaminyl cyclase inhibitors