{"title":"Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy.","authors":"Mingfei Wu, Yiquan Wu, Yuyuan Jin, Xinfei Mao, Shenxin Zeng, Hengyuan Yu, Jingyu Zhang, Yuheng Jin, Yizhe Wu, Tengfei Xu, Yong Chen, Yuwei Wang, Xiaojun Yao, Jinxin Che, Wenhai Huang, Xiaowu Dong","doi":"10.1021/acs.jmedchem.4c00644","DOIUrl":null,"url":null,"abstract":"<p><p>HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC <b>C3</b> was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. <b>C3</b> demonstrated significant HPK1 degradation with a DC<sub>50</sub> of 21.26 nM, excellent oral absorption with a <i>C</i><sub>max</sub> of 10,899.92 ng/mL, and a bioavailability (<i>F</i> %) of 81.7%. <b>C3</b> also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of <b>C3</b> 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 <b>C3</b> in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that <b>C3</b>, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-08-22","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://doi.org/10.1021/acs.jmedchem.4c00644","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC C3 was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. C3 demonstrated significant HPK1 degradation with a DC50 of 21.26 nM, excellent oral absorption with a Cmax of 10,899.92 ng/mL, and a bioavailability (F %) of 81.7%. C3 also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of C3 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 C3 in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that C3, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.
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.