Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects.

Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4, which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay.