Substrate-mimetic pyrimidinamines inhibit both glutaminyl cyclases and lower pE-CD47
- Structure-guided, substrate-mimetic design produced methylimidazolylethyl-pyrimidinamines that inhibit both secretory (sQC) and Golgi (gQC) glutaminyl cyclase.
- SAR led to compound 25, which also stabilized both enzymes in thermal shift assays; the sQC complex shows zinc coordination and a hydrogen bond to Gln304.
- In MDA-MB-231 cells, 25 cut surface pyroglutamate-CD47 without lowering total CD47, and it was clean against a 14-metalloenzyme panel.
💡 Points Based on the abstract
Zinc binders usually raise metalloenzyme selectivity worries, so a clean 14-enzyme panel is reassuring, though it was run at one high concentration and omits MMPs and HDACs I'd want to see. The real question is the pE-CD47 readout: does it translate into more macrophage phagocytosis? A functional assay would show whether this is more than a biomarker shift.
📄 Paper · European Journal of Medicinal Chemistry (Elsevier) ↗ Discovery of methylimidazolylethyl-pyrimidinamine derivatives as new glutaminyl cyclase inhibitors