Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome
Language English Country France Media print-electronic
Document type Journal Article
PubMed
32731189
DOI
10.1016/j.ejmech.2020.112636
PII: S0223-5234(20)30608-5
Knihovny.cz E-resources
- Keywords
- Bruton’s tyrosine kinase, Protein kinase, Scaffold hopping, Selectivity, Spleen tyrosine kinase,
- MeSH
- Phosphorylation MeSH
- Indazoles administration & dosage pharmacology MeSH
- Protein Kinase Inhibitors administration & dosage pharmacology MeSH
- Syk Kinase antagonists & inhibitors MeSH
- Humans MeSH
- Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors MeSH
- Proto-Oncogene Proteins c-bcr metabolism MeSH
- Pyrazines administration & dosage pharmacology MeSH
- Signal Transduction drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine MeSH Browser
- BCR protein, human MeSH Browser
- Indazoles MeSH
- Protein Kinase Inhibitors MeSH
- Syk Kinase MeSH
- Agammaglobulinaemia Tyrosine Kinase MeSH
- Proto-Oncogene Proteins c-bcr MeSH
- Pyrazines MeSH
- SYK protein, human MeSH Browser
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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