Abstract 1814: Development and evaluation of Hsp90β-selective inhibitors to overcome the safety challenges associated with pan-Hsp90 inhibitors

Abstract The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. More than 20 small-molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms (Hsp90a, Hsp90β, Grp94 and TRAP-1). Most of these clinical trials have failed as pan-Inhibition of Hsp90 appears to be detrimental with toxicities reported alongside induction of the pro-survival heat shock response, which leads to additional dosing challenges/toxicities. The cytosolic Hsp90 isoforms Hsp90a and Hsp90β are the major contributors to cancer growth/survival. It has been established that inhibition of Hsp90a is associated with cardiac toxicity, retinal toxicity, and induction of the heat shock response. Therefore, the development of Hsp90β -selective inhibitors represents an alternative approach for the treatment of cancer with limited side effects. Towards this goal, Hsp90β-selective inhibitors that exhibit 150-fold selectivity over Hsp90a have been developed, which exhibit efficacy against select cancers while overcoming the safety challenges associated with previous Hsp90 inhibitors. The results from such studies will be presented. Citation Format: Sanket Mishra, Tyelor Reynolds, Brian Blagg. Development and evaluation of Hsp90β-selective inhibitors to overcome the safety challenges associated with pan-Hsp90 inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1814.