Development of a First-in-Class Small-Molecule Inhibitor of the C-Terminal Hsp90 Dimerization.

Abstract

Heat shock proteins 90 (Hsp90) are promising therapeutic targets due to their involvement in stabilizing several aberrantly expressed oncoproteins. In cancerous cells, Hsp90 expression is elevated, thereby exerting antiapoptotic effects, which is essential for the malignant transformation and tumor progression. Most of the Hsp90 inhibitors (Hsp90i) under investigation target the ATP binding site in the N-terminal domain of Hsp90. However, adverse effects, including induction of the prosurvival resistance mechanism (heat shock response or HSR) and associated dose-limiting toxicity, have so far precluded their clinical approval. In contrast, modulators that interfere with the C-terminal domain (CTD) of Hsp90 do not inflict HSR. Since the CTD dimerization of Hsp90 is essential for its chaperone activity, interfering with the dimerization process by small-molecule protein-protein interaction inhibitors is a promising strategy for anticancer drug research. We have developed a first-in-class small-molecule inhibitor (5b) targeting the Hsp90 CTD dimerization interface, based on a tripyrimidonamide scaffold through structure-based molecular design, chemical synthesis, binding mode model prediction, assessment of the biochemical affinity, and efficacy against therapy-resistant leukemia cells. 5b reduces xenotransplantation of leukemia cells in zebrafish models and induces apoptosis in BCR-ABL1+ (T315I) tyrosine kinase inhibitor-resistant leukemia cells, without inducing HSR.

• Authors: Sanil Bhatia, Lukas Spanier, David Bickel, Niklas Dienstbier, Vitalij Woloschin, Melina Vogt, Henrik Pols, Beate Lungerich, Jens Reiners, Narges Aghaallaei, Daniela Diedrich, Benedikt Frieg, Julian Schliehe-Diecks, Bertan Bopp, Franziska Lang, Mohanraj Gopalswamy, Jennifer Loschwitz, Baubak Bajohgli, Julia Skokowa, Arndt Borkhardt, Julia Hauer, Finn K Hansen, Sander H J Smits, Joachim Jose, Holger Gohlke, Thomas Kurz
• Journal: ACS central science (ACS Cent Sci) Vol. 8 Issue 5 Pg. 636-655 (May 25 2022) ISSN: 2374-7943 [Print] United States
• PMID: 35647282 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Published by American Chemical Society.