Discovery of a New Isoxazole-3-hydroxamate Based Histone Deacetylase 6 Inhibitor SS-208 with Anti-tumor Activity in Syngeneic Melanoma Mouse Models

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F19%3A10396421" target="_blank" >RIV/00216208:11310/19:10396421 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/19:00510398

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4xNPSvbXRZ" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4xNPSvbXRZ</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.9b00946" target="_blank" >10.1021/acs.jmedchem.9b00946</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of a New Isoxazole-3-hydroxamate Based Histone Deacetylase 6 Inhibitor SS-208 with Anti-tumor Activity in Syngeneic Melanoma Mouse Models

Popis výsledku v původním jazyce

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

Název v anglickém jazyce

Discovery of a New Isoxazole-3-hydroxamate Based Histone Deacetylase 6 Inhibitor SS-208 with Anti-tumor Activity in Syngeneic Melanoma Mouse Models

Popis výsledku anglicky

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/ED1.1.00%2F02.0109" target="_blank" >ED1.1.00/02.0109: Biotechnologické a biomedicínské centrum Akademie věd a Univerzity Karlovy</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

62

Číslo periodika v rámci svazku

18

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

21

Strana od-do

8557-8577

Kód UT WoS článku

000488334500012

EID výsledku v databázi Scopus

2-s2.0-85072641509