发现 7H-吡咯并[2,3-d]嘧啶衍生物作为有效的造血祖细胞激酶 1（HPK1）抑制剂。
Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.
机构信息
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 100049, China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 100049, China.
出版信息
Eur J Med Chem. 2023 Jun 5;254:115355. doi: 10.1016/j.ejmech.2023.115355. Epub 2023 Apr 10.
Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cells and is a negative regulator of T cell receptor (TCR) signaling. Recent studies have demonstrated that HPK1 is a promising therapeutic target for cancer immunotherapy. However, despite significant progress in the development of HPK1 inhibitors, none of them has been approved for cancer therapy. Development of HPK1 inhibitors with a structurally distinct scaffold is still needed. Herein, we describe the design and synthesis of a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d]pyrimidine scaffold, exemplified by 31. Compound 31 showed potent inhibitory activity against HPK1 with an IC value of 3.5 nM and favorable selectivity within a panel of kinases. It also potently inhibited the phosphorylation level of SLP76, a substrate of HPK1, and enhanced the IL-2 secretion in Jurkat cells (human T cell leukemia). Our findings provide new clues for further optimization and development to generate HPK1 inhibitors for cancer immunotherapy.
造血祖细胞激酶 1（HPK1）主要在造血细胞中表达，是 T 细胞受体（TCR）信号的负调节剂。最近的研究表明，HPK1 是癌症免疫治疗的一个很有前途的治疗靶点。然而，尽管在开发 HPK1 抑制剂方面取得了重大进展，但没有一种被批准用于癌症治疗。仍需要开发具有结构独特支架的 HPK1 抑制剂。本文描述了一系列具有 7H-吡咯并[2,3-d]嘧啶支架的 HPK1 抑制剂的设计和合成，以化合物 31 为例。化合物 31 对 HPK1 表现出很强的抑制活性，IC 值为 3.5 nM，在一组激酶中具有良好的选择性。它还能有效抑制 HPK1 的底物 SLP76 的磷酸化水平，并增强 Jurkat 细胞（人 T 细胞白血病）中 IL-2 的分泌。我们的研究结果为进一步优化和开发用于癌症免疫治疗的 HPK1 抑制剂提供了新的线索。
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