Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
32731189
DOI
10.1016/j.ejmech.2020.112636
PII: S0223-5234(20)30608-5
Knihovny.cz E-zdroje
- Klíčová slova
- Bruton’s tyrosine kinase, Protein kinase, Scaffold hopping, Selectivity, Spleen tyrosine kinase,
- MeSH
- fosforylace MeSH
- indazoly aplikace a dávkování farmakologie MeSH
- inhibitory proteinkinas aplikace a dávkování farmakologie MeSH
- kinasa Syk antagonisté a inhibitory MeSH
- lidé MeSH
- proteinkinasa BTK antagonisté a inhibitory MeSH
- protoonkogenní proteiny c-bcr metabolismus MeSH
- pyraziny aplikace a dávkování farmakologie MeSH
- signální transdukce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine MeSH Prohlížeč
- BCR protein, human MeSH Prohlížeč
- indazoly MeSH
- inhibitory proteinkinas MeSH
- kinasa Syk MeSH
- proteinkinasa BTK MeSH
- protoonkogenní proteiny c-bcr MeSH
- pyraziny MeSH
- SYK protein, human MeSH Prohlížeč
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.
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