계명대학교 의학도서관 Repository

Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay

Metadata Downloads
Author(s)
Hye Yun ChaeSun You ParkSonam JhaSunil K. GuptaMikyung KimEunyoung HaYoung Ho Seo
Keimyung Author(s)
Ha, Eun Young
Department
Dept. of Biochemistry (생화학)
Journal Title
Eur J Med Chem
Issued Date
2022
Volume
240
Keyword
Hsp90HDAC6Lung cancerResistanceSmall moleculeDrug design
Abstract
HDAC6 and Hsp90, existing as a cytosolic complex play an important role in maintaining the protein homeostasis. The interplay of HDAC6 and Hsp90 has attracted wide attention due to their important role and promise as therapeutic targets in malignant cancers. Therefore, the discovery of dual inhibitors targeting HDAC6 and Hsp90 is of high importance. In the present study, we describe the design, synthesis, and biological evaluation of bifunctional inhibitors against HDAC6 and Hsp90 interplay. In particular, compound 6e shows a significant inhibitory activity against both HDAC6 and Hsp90 with IC50 values of 106 nM and 61 nM, respectively. Compound 6e promotes the acetylation of HDAC6 substrate proteins such as α-tubulin and Hsp90 via HDAC6 inhibition, and also induces the degradation of Hsp90 clients such as Her2, EGFR, Met, Akt, and HDAC6 via Hsp90 inhibition. Compound 6e consequently furnishes potent antiproliferative effect on gefitinib-resistant H1975 non-small cell lung cancer (NSCLC) with a GI50 value of 1.7 μM. In addition, compound 6e successfully achieved significant tumor growth inhibition in H1975 NSCLC xenograft model without noticeable abnormal behavior, body weight changes, and apparent ocular toxicity. We conclude that compound 6e constitutes an excellent tool as well as a valuable lead for assessment of Hsp90 and HDAC6 dual inhibition with a single molecule.
Keimyung Author(s)(Kor)
하은영
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
0223-5234
Source
https://www.sciencedirect.com/science/article/abs/pii/S0223523422004846
DOI
10.1016/j.ejmech.2022.114582
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44372
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
Authorize & License
  • Authorize공개
  • EmbargoForever
Files in This Item:
  • There are no files associated with this item.

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.