Abstract
Spleen tyrosine kinase (Syk) is an important oncogene and signal transduction mediator that is mainly expressed in hematopoietic cells. Syk plays a key role in the B cell receptor (BCR) signaling pathway. Abnormal activation of Syk is closely related to the occurrence and development of hematological malignancies. Therefore, Syk is a potential target for the treatment of various hematologic cancers. Starting from compound 6(Syk, IC50 = 15.8 μM), we performed fragment-based rational drug design for structural optimization based on the specific solvent-accessible region, hydrophobic region, and ribose region of Syk. This resulted in the discovery of a series of novel 3-(1H-benzo [d]imidazole-2-yl)-1H-pyrazol-4-amine Syk inhibitors, which led to the identification of 19q, a highly potent Syk inhibitor that exhibited excellent inhibitory activity on Syk enzyme (IC50 = 0.52 nM) and showed potency against several other kinases. In addition, compound 19q effectively reduced phosphorylation of downstream PLCγ2 level in Romos cells. And it also exhibited antiproliferative activity in multiple hematological tumour cells. More gratifyingly, 19q showed impressive efficacy at a low dosage (1 mg/kg/day) in the MV4-11 mouse xenograft model without affecting the body weight of the mice. These findings suggest that 19q is a promising new Syk inhibitor for treating blood cancers.
Published Version
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