The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(E)-picolinylidene androstane derivatives

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00639306" target="_blank" >RIV/61388963:_____/25:00639306 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1080/14756366.2025.2551979" target="_blank" >https://doi.org/10.1080/14756366.2025.2551979</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1080/14756366.2025.2551979" target="_blank" >10.1080/14756366.2025.2551979</a>

Jazyk výsledku

angličtina

Název v původním jazyce

The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(E)-picolinylidene androstane derivatives

Popis výsledku v původním jazyce

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17 alpha-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17 alpha-picolyl androstane with a C3-oxime modification, was determined at 1.7 & Aring, resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17 alpha-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP+ cofactor, while the C17 alpha-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

Název v anglickém jazyce

The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(E)-picolinylidene androstane derivatives

Popis výsledku anglicky

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17 alpha-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17 alpha-picolyl androstane with a C3-oxime modification, was determined at 1.7 & Aring, resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17 alpha-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP+ cofactor, while the C17 alpha-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

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/LX22NPO5102" target="_blank" >LX22NPO5102: Národní ústav pro výzkum rakoviny</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Journal of Enzyme Inhibition and Medicinal Chemistry

ISSN

1475-6366

e-ISSN

1475-6374

Svazek periodika

40

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

20

Strana od-do

2551979

Kód UT WoS článku

001564429000001

EID výsledku v databázi Scopus

2-s2.0-105015068341