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

0535283 - ÚEB 2021 RIV FR eng J - Journal Article
Jorda, Radek - Krajčovičová, S. - Králová, P. - Soural, M. - Kryštof, Vladimír
Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome.
European Journal of Medicinal Chemistry. Roč. 204, OCT 15 (2020), č. článku 112636. ISSN 0223-5234. E-ISSN 1768-3254
Institutional support: RVO:61389030
Keywords : Bruton's tyrosine kinase * Protein kinase * Scaffold hopping * Selectivity * Spleen tyrosine kinase
OECD category: Hematology
Impact factor: 6.514, year: 2020
Method of publishing: Open access
http://doi.org/10.1016/j.ejmech.2020.112636

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.
Permanent Link: http://hdl.handle.net/11104/0313353