Global Drug R&D Center, Huadong Medicine, Hangzhou 310011, P. R. China.
J Med Chem. 2024 Nov 14;67(21):18682-18698. doi: 10.1021/acs.jmedchem.4c01906. Epub 2024 Oct 24.
Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound with high selectivity and potency. showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.
造血祖细胞激酶 1（HPK1，MAP4K1）是一种丝氨酸/苏氨酸（SER/THR）激酶，已被鉴定为 T 细胞受体信号的负免疫调节剂。剥夺 HPK1 的功能会抑制肿瘤生长，为癌症免疫治疗提供了一种有吸引力的策略。在此，我们提出了一种新型基于 PROTAC 的 HPK1 降解化合物，具有高选择性和高效性。 表现出 SLP-76 磷酸化的剂量依赖性抑制和 IL-2 和 IFN-γ 的诱导。与其他抑制剂相比， 在 MC38 模型中表现出良好的疗效和有利的安全性特征。具体而言，以 0.5mg/kg 的剂量口服 与抗 PD1 联合使用可导致 TGI 值为 91.0%的显著抑制。此外， 表现出低心脏毒性风险和宽安全窗口。这项研究工作表明， 是癌症单药和联合免疫治疗的有前途的临床前候选物（PCC）。
