{"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, Dongzhou Liu","doi":"10.1021/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 <b>DD205-291</b> with high selectivity and potency. <b>DD205-291</b> showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, <b>DD205-291</b> exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of <b>DD205-291</b> at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, <b>DD205-291</b> exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that <b>DD205-291</b> is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.","PeriodicalId":6,"journal":{"name":"ACS Applied Nano Materials","volume":null,"pages":null},"PeriodicalIF":5.3000,"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, Dongzhou Liu\",\"doi\":\"10.1021/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 <b>DD205-291</b> with high selectivity and potency. <b>DD205-291</b> showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, <b>DD205-291</b> exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of <b>DD205-291</b> at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, <b>DD205-291</b> exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that <b>DD205-291</b> is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.\",\"PeriodicalId\":6,\"journal\":{\"name\":\"ACS Applied Nano Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-10-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Nano Materials\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c01906\",\"RegionNum\":2,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Nano Materials","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01906","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","Score":null,"Total":0}
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.
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.
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