Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach

Hsp90
is a new promising target for cancer treatment. Many inhibitors
have been discovered as therapeutic agents, and some have passed Phase
I and II. However, no one is approved by FDA yet. Novel and druggable
Hsp90 inhibitors are still demanding. Here, we report a new way to
discover high potent Hsp90 inhibitors as antinasopharyngeal carcinoma
agents through assembling fragments. With chemotyping analysis, we
extract seven chemotypes from 3482 known Hsp90 inhibitors, screen
500 fragments that are compatible with the chemotypes, and confirm
15 anti-Hsp90 fragments. Click chemistry is employed to construct
172 molecules and synthesize 21 compounds among them. The best inhibitor
3d was further optimized and resulted in more potent 4f (IC50 = 0.16 μM). In vitro and in vivo experiments confirmed that 4f is a promising agent against nasopharyngeal
carcinoma. This study may provide a strategy in discovering new ligands
against targets without well-understood structures.