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

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.

01 Oct 2019·European Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Lynch, Caitlin ; Xue, Fengtian ; Liang, Dongdong ; Wang, Hongbing ; Xia, Menghang ; Li, Linhao ; Ai, Yong ; Mackowiak, Bryan ; Yin, Yue ; Hedrich, William D ; Heyward, Scott

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 E_MAX 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Hodgkin Lymphoma	Preclinical	-	-	01 Oct 2019
Diffuse Large B-Cell Lymphoma	Discovery	United States	University of Maryland	04 Mar 2021

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