Emerging opportunities and challenges in small molecule development for non-HSP90 chaperones.

Heat shock proteins (HSPs) are pivotal regulators of proteostasis, with their dysregulation implicated in cancer, neurodegeneration, and infectious diseases. Significant progress has been made in targeting HSP90, particularly in oncology, where inhibitors have demonstrated considerable therapeutic potential and validated HSP90 as a promising drug target. However, other HSP families remain relatively underexplored as drug targets despite their critical biological roles.

Design and Synthesis of 7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme.

The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound with 38-fold enhanced PP5 selectivity (PP2A/5 IC = 33.