RESUMO
This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.
Assuntos
Cisteína Endopeptidases , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Estrutura MolecularRESUMO
This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub-nanomolar inhibitor of Legumain.