Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310058, P. R. China.
J Med Chem. 2024 Aug 22;67(16):13852-13878. doi: 10.1021/acs.jmedchem.4c00644. Epub 2024 Jul 31.
HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. demonstrated significant HPK1 degradation with a DC of 21.26 nM, excellent oral absorption with a of 10,899.92 ng/mL, and a bioavailability ( %) of 81.7%. also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of is attributed to the inhibition of SLP76 and NF-κB signaling pathways, as well as the enhancement of MAPK signaling pathway transduction. In vivo efficacy study demonstrated that oral administration of in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that , a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.
HPK1 是 T 细胞受体的一种知名负调控因子，异常激活时可导致 T 细胞功能障碍。在本研究中，通过优化弹头、连接子和 CRBN 配体的理化性质，设计并合成了一种 PROTAC。该化合物对 HPK1 具有显著的降解作用，DC50 为 21.26 nM，具有良好的口服吸收性， 为 10,899.92 ng/mL，生物利用度（%）为 81.7%。该化合物还表现出降解选择性和有效的免疫激活作用。蛋白质组学和 WB 分析表明， 的免疫激活作用归因于 SLP76 和 NF-κB 信号通路的抑制，以及 MAPK 信号通路转导的增强。体内药效学研究表明，PDL1 抗体联合口服给予 可显著抑制肿瘤生长（肿瘤生长抑制率=65.58%）。这些发现表明，作为一种新型的 HPK1 PROTAC， 有望成为肿瘤免疫治疗的一种治疗剂。
