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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-10-24 DOI:10.1021/acs.jmedchem.4c0190610.1021/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 and Dongzhou Liu*,

{"title":"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","authors":"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 and Dongzhou Liu*, ","doi":"10.1021/acs.jmedchem.4c0190610.1021/acs.jmedchem.4c01906","DOIUrl":null,"url":null,"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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"18682–18698 18682–18698"},"PeriodicalIF":6.8000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy\",\"authors\":\"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 and Dongzhou Liu*, \",\"doi\":\"10.1021/acs.jmedchem.4c0190610.1021/acs.jmedchem.4c01906\",\"DOIUrl\":null,\"url\":null,\"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.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"67 21\",\"pages\":\"18682–18698 18682–18698\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01906\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01906","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

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。具体而言，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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

查看原文本刊更多论文

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

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.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.