TY  - JOUR
AU  - Bhatia, Sanil
AU  - Spanier, Lukas
AU  - Bickel, David
AU  - Dienstbier, Niklas
AU  - Woloschin, Vitalij
AU  - Vogt, Melina
AU  - Pols, Henrik
AU  - Lungerich, Beate
AU  - Reiners, Jens
AU  - Aghaallaei, Narges
AU  - Diedrich, Daniela
AU  - Frieg, Benedikt
AU  - Schliehe-Diecks, Julian
AU  - Bopp, Bertan
AU  - Lang, Franziska
AU  - Gopalswamy, Mohanraj
AU  - Loschwitz, Jennifer
AU  - Bajohgli, Baubak
AU  - Skokowa, Julia
AU  - Borkhardt, Arndt
AU  - Hauer, Julia
AU  - Hansen, Finn K.
AU  - Smits, Sander H. J.
AU  - Jose, Joachim
AU  - Gohlke, Holger
AU  - Kurz, Thomas
TI  - Development of a First-in-Class Small-Molecule Inhibitor of the C-Terminal Hsp90 Dimerization
JO  - ACS central science
VL  - 8
IS  - 5
SN  - 2374-7943
CY  - Washington, DC
PB  - ACS Publ.
M1  - FZJ-2022-02209
SP  - 636–655
PY  - 2022
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 35647282
UR  - <Go to ISI:>//WOS:000806002600015
DO  - DOI:10.1021/acscentsci.2c00013
UR  - https://juser.fz-juelich.de/record/907780
ER  -