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.

Department of Organic Chemistry Faculty of Science Palacký University 17 Listopadu 12 77146 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

Laboratory of Growth Regulators Palacký University and Institute of Experimental Botany The Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic

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