Hsp90-targeting Chimeras

Hsp90 is a molecular chaperone and key regulator of proteostasis under physiological and stress conditions^[1]. Mechanistically, mammalian cytosolic Hsp90α and Hsp90β interact with a large fraction of the proteome, but disease-state cells may depend more strongly on one isoform^[1]. This isoform distinction matters because Hsp90β is constitutively expressed and essential for early mouse development, whereas Hsp90α is stress-inducible and not necessary for survivability^[1]. Compared with related isoforms, selective design remains difficult because Hsp90α and Hsp90β share 95% identity in the N-terminal ATP-binding site and differ by only two amino acid residues^[2]. In breast cancer models, BP3 used a PROTAC strategy to induce potent, selective, CRBN-dependent HSP90 degradation and inhibit human breast cancer cell growth^[3]. X10g further refined this approach by selectively degrading Hsp90α without affecting Hsp90β while maintaining antitumor activity in breast cancer models^[4]. For experimental applications, HEMTACs bridge target proteins to HSP90 to drive intracellular protein degradation^[5]. HIM-PROTACs extended this concept by degrading GPX4 through HSP90-mediated ubiquitin-proteasomal degradation to trigger ferroptosis in HT-1080 cells^[6].