7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00559439" target="_blank" >RIV/68378050:_____/22:00559439 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/23:00558179 RIV/00216208:11150/22:10445938 RIV/00216208:11160/22:10445938 RIV/00179906:_____/22:10445938

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/abs/pii/S0223523422004822?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S0223523422004822?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2022.114580" target="_blank" >10.1016/j.ejmech.2022.114580</a>

Jazyk výsledku

angličtina

Název v původním jazyce

7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties

Popis výsledku v původním jazyce

Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three high-lighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 mu M. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.

Název v anglickém jazyce

7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties

Popis výsledku anglicky

Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three high-lighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 mu M. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10601 - Cell biology

Projekt

<a href="/cs/project/EF18_069%2F0010046" target="_blank" >EF18_069/0010046: Předaplikační výzkum inovativních léčiv a medicínských technologií</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

240

Číslo periodika v rámci svazku

June

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

20

Strana od-do

114580

Kód UT WoS článku

000826524000002

EID výsledku v databázi Scopus

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