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.

脾脏酪氨酸激酶（SYK）和布鲁顿酪氨酸激酶（BTK）是具有过度激活的B细胞受体（BCR）信号传导途径的人类血液系统恶性肿瘤的诱人靶标。Entospletinib是一种SYK抑制剂，已被评估为临床候选药物。我们设计并制备了五个等位基因，其中恩斯普替尼的咪唑并[1,2- a ]吡嗪支架被更改为吡唑并[3,4- d ]嘧啶，吡咯并[3,2- d ]嘧啶，咪唑并[4,5- b ]吡啶，咪唑并[4，5- c ]吡啶和嘌呤。最后两个等位基因是最有效的SYK抑制剂，IC ₅₀值在中纳摩尔范围内。重要的是，三种化合物还比恩替普替尼更有效地抑制BTK。然后进一步的实验表明，有效化合物在Ramos细胞中抑制了BCR信号传导。初步的激酶抑制筛选也显示LCK和SRC是另外的靶标。我们的结果进一步支持了以下假设：以多激酶为靶标的化合物可以在治疗B淋巴瘤中产生更强的应答。