设计合成了1H-吡唑并[3,4-d]嘧啶衍生物作为造血前体激酶1（HPK1）抑制剂。
Design and synthesis of 1H-pyrazolo[3,4-d]pyrimidine derivatives as hematopoietic progenitor kinase 1 (HPK1) inhibitors.
发表日期：2023 Aug 26
作者：
Junjie Zhang, Yan Li, Haotian Tang, Qianqian Zhou, Linjiang Tong, Jian Ding, Hua Xie, Bing Xiong, Tongchao Liu
来源：
BIOORGANIC CHEMISTRY
摘要：
免疫检查点抑制剂在肿瘤治疗中取得巨大成功，但中等响应率限制了其广泛应用。造血前体激酶1（HPK1）作为T细胞受体的重要负性调控因子，被确定为增强抗肿瘤免疫的有前景靶点。然而，开发选择性HPK1抑制剂仍然具有挑战性。在此，我们报道了一系列基于结构的有理设计的1H-吡唑并[3,4-d]嘧啶衍生物作为HPK1抑制剂。最佳化合物10n以IC50值为29.0 nM显著抑制了HPK1以及浓度为0.1 μM时对SLP76的磷酸化。此外，化合物10n对包括同一MAP4K家族中的GLK在内的25个激酶表现出良好的选择性。综上，本研究提供了一种新型、有效且选择性的HPK1抑制剂，可作为癌症免疫治疗未来开发的引领化合物。版权所有 © 2023 Elsevier Inc. 保留所有权利。
Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC50 value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 μM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.Copyright © 2023 Elsevier Inc. All rights reserved.