Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3′-pyrazolyl)-2-amino-pyrimidine scaffold. Extensive study of structure-activity relationships led to the identification of , a highly potent Syk inhibitor (IC = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines. Additionally, effectively inhibited Syk phosphorylation and downstream signaling mediators of the BCR in treated cells. In pharmacokinetics studies, , displayed good pharmacokinetics properties, with linear exposure with dose and excellent oral bioavailability. These findings suggest that is a promising new Syk inhibitor for treating BCR-dependent hematological cancers.

中文翻译：

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4-吡唑基-2-氨基嘧啶衍生物作为有效脾酪氨酸激酶 (SYK) 抑制剂的发现和优化

脾酪氨酸激酶 (Syk) 是 B 细胞受体 (BCR) 信号通路的关键信号转导介质。异常的 BCR 信号传导在 B 细胞源性血液恶性肿瘤的发生和发展中起着关键作用，因此，Syk 代表了抑制 BCR 信号传导的潜在靶点，从而对这些癌症产生治疗效果。在此，我们描述了一系列具有 4-(3'-吡唑基)-2-氨基-嘧啶支架的新型 SYK 抑制剂。对结构-活性关系的广泛研究导致了 的鉴定，这是一种高效 Syk 抑制剂 (IC = 3 nM)，在一组测试的激酶中具有高选择性，并且在 SYK 依赖性 BaF3-TEL/SYK 细胞和其他 BCR 依赖性血液肿瘤细胞系。此外，还可有效抑制处理细胞中的 Syk 磷酸化和 BCR 下游信号传导介质。在药代动力学研究中，显示出良好的药代动力学特性，暴露量与剂量呈线性关系，并且具有出色的口服生物利用度。这些发现表明，这是一种有前途的新型 Syk 抑制剂，可用于治疗 BCR 依赖性血液癌症。