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 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.