Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F20%3A00535283" target="_blank" >RIV/61389030:_____/20:00535283 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/20:73604617

Výsledek na webu

<a href="http://doi.org/10.1016/j.ejmech.2020.112636" target="_blank" >http://doi.org/10.1016/j.ejmech.2020.112636</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2020.112636" target="_blank" >10.1016/j.ejmech.2020.112636</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome

Popis výsledku v původním jazyce

Spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK) are attractive targets in human haematological malignancies with excessively activated B-cell receptor (BCR) signalling pathways. Entospletinib is a SYK inhibitor that has been evaluated as a clinical candidate. We designed and prepared five isosteres in which the imidazo[1,2-a]pyrazine scaffold of entospletinib was altered to pyrazolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine and purine. The last two isosteres were the most potent SYK inhibitors, with IC50 values in the mid-nanomolar range. Importantly, three compounds also inhibited BTK more effectively than did entospletinib. Further experiments then showed that BCR signalling was suppressed in Ramos cells by the potent compounds. Preliminary kinase inhibition screening also revealed LCK and SRC as additional targets. Our results further support the hypothesis that multikinase targeting compounds could produce more robust responses in the treatment of B lymphoid neoplasms.

Název v anglickém jazyce

Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome

Popis výsledku anglicky

Spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK) are attractive targets in human haematological malignancies with excessively activated B-cell receptor (BCR) signalling pathways. Entospletinib is a SYK inhibitor that has been evaluated as a clinical candidate. We designed and prepared five isosteres in which the imidazo[1,2-a]pyrazine scaffold of entospletinib was altered to pyrazolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine and purine. The last two isosteres were the most potent SYK inhibitors, with IC50 values in the mid-nanomolar range. Importantly, three compounds also inhibited BTK more effectively than did entospletinib. Further experiments then showed that BCR signalling was suppressed in Ramos cells by the potent compounds. Preliminary kinase inhibition screening also revealed LCK and SRC as additional targets. Our results further support the hypothesis that multikinase targeting compounds could produce more robust responses in the treatment of B lymphoid neoplasms.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

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

—

Svazek periodika

204

Číslo periodika v rámci svazku

OCT 15

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

10

Strana od-do

112636

Kód UT WoS článku

000573916100035

EID výsledku v databázi Scopus

2-s2.0-85088506314