Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials Pub Date : 2024-10-24 DOI:10.1021/acs.jmedchem.4c01906

Zhimin Zhang, Liubin Guo, Mengting Zhao, Hao Pan, Zhao Dong, Ling Wang, Xi Yang, Zhiping Zhang, Mengqiang Wu, Yujie Chang, Yacheng Yang, Linan Sun, Sirui Liu, Rongyao Zhu, Haowen Zheng, Xinyu Dai, Xiaohua Zhang, Chunhua Jiang, Zhuangzhi Zhu, Yuchen Zhang, Dongzhou Liu

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引用次数: 0

Abstract

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 DD205-291 with high selectivity and potency. DD205-291 showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, DD205-291 exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of DD205-291 at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.

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发现基于 PROTAC 的新型 HPK1 降解剂，具有用于癌症免疫疗法的高效力和高选择性

造血祖细胞激酶 1（HPK1，MAP4K1）是一种丝氨酸/苏氨酸（SER/THR）激酶，已被确定为 T 细胞受体信号转导的负性免疫调节剂。剥夺 HPK1 的功能可抑制肿瘤生长，为癌症免疫疗法提供了一种极具吸引力的策略。在此，我们展示了一种基于 PROTAC 的新型 HPK1 降解剂化合物 DD205-291，该化合物具有高选择性和高效力。DD205-291 对 SLP-76 磷酸化有剂量依赖性抑制作用，并能诱导 IL-2 和 IFN-γ。与其他抑制剂相比，DD205-291在MC38模型中表现出良好的疗效和安全性。具体来说，口服 0.5 mg/kg 剂量的 DD205-291 与抗 PD1 联合使用可显著抑制肿瘤生长，TGI 值达 91.0%。此外，DD205-291 显示出较低的心脏毒性风险和较宽的安全窗。这项研究工作表明，DD205-291 是一种很有前途的临床前候选药物（PCC），可用于癌症的单药和联合免疫疗法。

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来源期刊

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.