Potent andSelective Human Constitutive AndrostaneReceptor 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 EC₅₀ of 0.35 μM and <i>E</i>_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 <i>in vivo</i>.