Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies
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 <b>6i</b>, <b>6k</b> (DL5055), and <b>7e</b>, showed significantly improved activating potency for hCAR. Particularly, DL5055 activates hCAR with an EC<sub>50</sub> of 0.35 μM and <i>E</i><sub>MAX</sub> 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 <i>in vivo</i>.
Authors
- William D. Hedrich
- Scott Heyward (ORCID: https://orcid.org/0000-0001-7805-3522)
- Menghang Xia (ORCID: https://orcid.org/0000-0001-7285-8469)
- Caitlin Lynch
- Alexander D. MacKerell (ORCID: https://orcid.org/0000-0001-8287-6804)
- Srilatha Sakamuru (ORCID: https://orcid.org/0000-0002-9693-1832)
- Fengtian Xue (ORCID: https://orcid.org/0000-0002-4132-9887)
- Hongbing Wang (ORCID: https://orcid.org/0000-0002-6224-6888)
- Wenbo Yu (ORCID: https://orcid.org/0000-0001-6962-5314)
- Zhihui Li (ORCID: https://orcid.org/0000-0002-9872-7624)
- Dongdong Liang (ORCID: https://orcid.org/0000-0002-1136-231X)
- Yong Ai (ORCID: https://orcid.org/0000-0002-7598-7992)
- Linhao Li (ORCID: https://orcid.org/0000-0002-3207-9740)
- Ismael Watts-Ouattara
Institutions
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Université Bourgogne Franche-Comté (FR)
- National Center for Advancing Translational Sciences (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02064
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute
- National Institute of General Medical Sciences
- National Center for Advancing Translational Sciences