PUBLICATION
Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders
- Authors
- Dernovšek, J., Goričan, T., Gedgaudas, M., Zajec, Ž., Urbančič, D., Jug, A., Skok, Ž., Sturtzel, C., Distel, M., Grdadolnik, S.G., Babu, K., Panchamatia, A., Stachowski, T.R., Fischer, M., Ilaš, J., Zubrienė, A., Matulis, D., Zidar, N., Tomašič, T.
- ID
- ZDB-PUB-241011-18
- Date
- 2024
- Source
- European Journal of Medicinal Chemistry 280: 116934116934 (Journal)
- Registered Authors
- Distel, Martin, Sturtzel, Caterina
- Keywords
- Cancer, Hsp90, Isoform selectivity, Topoisomerase II
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/chemical synthesis
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- DNA Topoisomerases, Type II*/metabolism
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- HSP90 Heat-Shock Proteins*/antagonists & inhibitors
- HSP90 Heat-Shock Proteins*/metabolism
- Humans
- Molecular Structure
- Structure-Activity Relationship
- Topoisomerase II Inhibitors*/chemical synthesis
- Topoisomerase II Inhibitors*/chemistry
- Topoisomerase II Inhibitors*/pharmacology
- Zebrafish*
- PubMed
- 39388906 Full text @ Eur. J. Med. Chem.
Citation
Dernovšek, J., Goričan, T., Gedgaudas, M., Zajec, Ž., Urbančič, D., Jug, A., Skok, Ž., Sturtzel, C., Distel, M., Grdadolnik, S.G., Babu, K., Panchamatia, A., Stachowski, T.R., Fischer, M., Ilaš, J., Zubrienė, A., Matulis, D., Zidar, N., Tomašič, T. (2024) Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders. European Journal of Medicinal Chemistry. 280:116934116934.
Abstract
Due to their impact on several oncogenic client proteins, the Hsp90 family of chaperones has been widely studied for the development of potential anticancer agents. Although several Hsp90 inhibitors have entered clinical trials, most were unsuccessful because they induced a heat shock response (HSR). This issue can be circumvented by using isoform-selective inhibitors, but the high similarity in the ATP-binding sites between the isoforms presents a challenge. Given that Hsp90 shares a conserved Bergerat fold with bacterial DNA gyrase B and human topoisomerase IIα, we repurposed our ATP-competitive inhibitors of these two proteins for Hsp90 inhibition. We virtually screened a library of in-house inhibitors and identified eleven hits for evaluation of Hsp90 binding. Among these, compound 11 displayed low micromolar affinity for Hsp90 and demonstrated a 12-fold selectivity for Hsp90β over its closest isoform, Hsp90α. Out of 29 prepared analogs, 16 showed a preference for Hsp90β over Hsp90α. Furthermore, eleven of these compounds inhibited the growth of several cancer cell lines in vitro. Notably, compound 24e reduced intracellular levels of Hsp90 client proteins in MCF-7 cells, leading to cell cycle arrest in the G0/G1 phase without inducing HSR. This inhibitor exhibited at least a 27-fold preference for Hsp90β and was selective against topoisomerase IIα, a panel of 22 representative protein kinases, and proved to be non-toxic in a zebrafish larvae toxicology model. Finally, molecular modeling, corroborated by STD NMR studies, and the binding of 24e to the S52A mutant of Hsp90α confirmed that the serine to alanine switch drives the selectivity between the two cytoplasmic isoforms.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping