2. Academic Validation
  3. Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies

Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies

  • Eur J Med Chem. 2019 Oct 1:179:84-99. doi: 10.1016/j.ejmech.2019.06.031.
Dongdong Liang 1,  Linhao Li 1,  Caitlin Lynch 2,  Bryan Mackowiak 1,  William D Hedrich 1,  Yong Ai 1,  Yue Yin 1,  Scott Heyward 3,  Menghang Xia 2,  Hongbing Wang 4,  Fengtian Xue 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, United States.
  • 2 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, United States.
  • 3 BioIVT, 1450 S Rolling Rd, Halethorpe, MD, 21227, United States.
  • 4 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, United States. Electronic address: [email protected].
  • 5 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, United States. Electronic address: [email protected].
PMID: 31247375 DOI: 10.1016/j.ejmech.2019.06.031
Abstract

The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with Other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by Cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human Constitutive Androstane Receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 μM and EMAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells.

Keywords

Chemotherapy; Co-culture; Cyclophosphamide; Human constitutive androstane receptor; Structure-activity relationship.

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