Click-chemistry microplate library speeds CDK2 hit-to-lead
- Structure-guided design fed a roughly 1800-member triazole library made by copper-catalyzed click chemistry in 96-well plates, with no purification.
- Crude mixtures went straight into a competitive fluorescence polarization assay; two screening rounds picked out actives.
- The lead, LL-K2in10, inhibits CDK2 in binding and enzymatic assays, and a co-crystal structure shows multiple hydrogen bonds explaining the SAR.
- In OVCAR3 cells it showed target engagement, lower Rb phosphorylation, reduced viability and altered cell cycle.
💡 Points Based on the abstract
Screening crude click mixtures is fast, but residual copper, unreacted azide or alkyne and aggregators can fake or mask binding, so my first move would be resynthesizing and purifying the top hits to confirm potency. Then selectivity: CDK2 over CDK1 and CDK9 is where ATP-site chemotypes usually fail, so I'd want a kinase panel and a head-to-head against established aminopyrazole or purine scaffolds.