Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-27 DOI:10.1021/acs.jmedchem.4c02064

Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue

{"title":"Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies","authors":"Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue","doi":"10.1021/acs.jmedchem.4c02064","DOIUrl":null,"url":null,"abstract":"Enhancement of the metabolic conversion of cyclophosphamide (CPA) increases its therapeutic effects. Activation of the human constitutive androstane receptor (hCAR) induces CYP2B6, a key enzyme responsible for CPA bioactivation. Based on our previous hCAR activator DL5016, we designed and synthesized a series of new hCAR activators. Compared to DL5016, three new compounds 6i, 6k (DL5055), and 7e, showed significantly improved activating potency for hCAR. Particularly, DL5055 activates hCAR with an EC50 of 0.35 μM and EMAX of 4.3, and does not activate hPXR and other related nuclear receptors. It induced the expression of CYP2B6 and caused the translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. DL5055 also induces the expression of Cyp2b10 (the mouse analog of human CYP2B6) in hCAR-transgenic mice. In addition, it significantly enhances the efficacy of CPA-based chemotherapy regimen, CHOP, in a coculture system and a mouse xenograft model in vivo.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"72 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-03-27","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.4c02064","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

Abstract

Enhancement of the metabolic conversion of cyclophosphamide (CPA) increases its therapeutic effects. Activation of the human constitutive androstane receptor (hCAR) induces CYP2B6, a key enzyme responsible for CPA bioactivation. Based on our previous hCAR activator DL5016, we designed and synthesized a series of new hCAR activators. Compared to DL5016, three new compounds 6i, 6k (DL5055), and 7e, showed significantly improved activating potency for hCAR. Particularly, DL5055 activates hCAR with an EC₅₀ of 0.35 μM and E_MAX of 4.3, and does not activate hPXR and other related nuclear receptors. It induced the expression of CYP2B6 and caused the translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. DL5055 also induces the expression of Cyp2b10 (the mouse analog of human CYP2B6) in hCAR-transgenic mice. In addition, it significantly enhances the efficacy of CPA-based chemotherapy regimen, CHOP, in a coculture system and a mouse xenograft model in vivo.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

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.