Screening under 0.1% of a library yields new QPCT/L inhibitor tool BI-3614
- QPCT and Golgi-bound QPCTL convert N-terminal glutamines to pyroglutamate, affecting Aβ oligomerization, chemokine stability and CD47–SIRPα signaling.
- A virtual screen selecting under 0.1% of an in-house library, based on similarity to bioactive conformations of known inhibitors, delivered new chemotypes and sped up hit discovery.
- Structure-guided optimization of a quinazolidinone series gave the cellular tool compound BI-3614, with improved activity over earlier inhibitors.
💡 Points
Screening under a tenth of a percent and still finding fresh chemotypes is the efficiency argument for conformation-based similarity searching. The old QPCT inhibitors leaned on metal-binding groups, so a new cell-active series is welcome for CD47 pyroglutamate biology. QPCT versus QPCTL selectivity is what I'd check first.