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Updated: May 20, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based
Dongdong Liang1, Linhao Li1, Yong Ai1
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, United States.
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.
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