2. Academic Validation
  3. Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome

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

  • Eur J Med Chem. 2020 Oct 15;204:112636. doi: 10.1016/j.ejmech.2020.112636.
Radek Jorda 1,  Soňa Krajčovičová 2,  Petra Králová 2,  Miroslav Soural 3,  Vladimír Kryštof 4
Affiliations

Affiliations

  • 1 Laboratory of Growth Regulators, Palacký University & Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900, Olomouc, Czech Republic.
  • 2 Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 77146, Olomouc, Czech Republic.
  • 3 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900, Olomouc, Czech Republic; Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 77146, Olomouc, Czech Republic.
  • 4 Laboratory of Growth Regulators, Palacký University & Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 78371, Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.
PMID: 32731189 DOI: 10.1016/j.ejmech.2020.112636
Abstract

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.

Keywords

Bruton’s tyrosine kinase; Protein kinase; Scaffold hopping; Selectivity; Spleen tyrosine kinase.

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