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New class of Hsp90 C-terminal domain inhibitors with anti-tumor properties against triple-negative breast cancer
ID
Zajec, Živa
(
Author
),
ID
Dernovšek, Jaka
(
Author
),
ID
Cingl, Jernej
(
Author
),
ID
Ogris, Iza
(
Author
),
ID
Gedgaudas, Marius
(
Author
),
ID
Zubrienė, Asta
(
Author
),
ID
Mitrović, Ana
(
Author
),
ID
Golič Grdadolnik, Simona
(
Author
),
ID
Gobec, Martina
(
Author
),
ID
Tomašič, Tihomir
(
Author
)
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MD5: 8DD2DFC653E196969675EFE5E7AD6FC6
URL - Source URL, Visit
https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00932
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Abstract
Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to Hsp90. The newly synthesized analogs showed increased antiproliferative activity in breast cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of Hsp90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap.
Language:
English
Keywords:
assays
,
cancer
,
cells
,
inhibitors
,
phenyls
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Publication status:
Published
Publication version:
Version of Record
Year:
2024
Number of pages:
Str. 12984–13018
Numbering:
Vol. 67, iss. 15
PID:
20.500.12556/RUL-160213
UDC:
615.2:616-006:576.3
ISSN on article:
1520-4804
DOI:
10.1021/acs.jmedchem.4c00932
COBISS.SI-ID:
203626243
Publication date in RUL:
23.08.2024
Views:
105
Downloads:
50
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Record is a part of a journal
Title:
Journal of medicinal chemistry
Shortened title:
J. med. chem.
Publisher:
American Chemical Society
ISSN:
1520-4804
COBISS.SI-ID:
512806681
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Secondary language
Language:
Slovenian
Keywords:
analize
,
zaviralci
,
fenili
,
rak dojk
,
rak
,
medicina
,
celice
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-1717
Name:
Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-50038
Name:
Nove terapije Ewingovega sarkoma, osnovane na zaviralcih Hsp90
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0010
Name:
Folding in dinamika biomolekularnih sistemov
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0420
Name:
Napredna imunološka zdravila in celični pristopi v farmaciji
Funder:
ARRS - Slovenian Research Agency
Project number:
J1-4400
Name:
Vrednotenje prehodnih stanj proteinov
Funder:
Other - Other funder or multiple funders
Funding programme:
Ministry of Education, Science and Sport (MIZŠ )
Project number:
OP20.05187
Acronym:
RI-SI-EATRIS
Funder:
EC - European Commission
Funding programme:
European Regional Development Fund
Acronym:
RI-SI-EATRIS
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