Identification and characterization of a novel nonsecosteroidal vitamin D receptor ligand

Vitamin D receptor (VDR) and its ligands play important roles in mineral/skeletal homeostasis, cell proliferation/differentiation, and modulation of immune responses. VDR ligands make attractive candidates for the treatment/prevention of osteoporosis, psoriasis, and cancer. The major issue with current analogs is hypercalcemia. As nonsteroidal therapeutic agents with fewer side effects have been made for androgen and estrogen receptors, nonsecosteroidal VDR ligands possessing beneficial effects may also be possible. Here we present a novel podocarpic acid-based nonsecosteroidal VDR ligand (VDRL-1). VDRL-1 bound to VDR with a Ki of ∼1.3 µM in competition binding assays. Data from binding and molecular docking suggest that VDRL-1 interacts with the same binding pocket as 1α,25-(OH)2 vitamin D3 (1,25-D3). In cell-based transcription assays, VDRL-1 reached the same maximal activity as 1,25-D3, albeit with an EC50 ∼1.0 µM. Likewise, VDRL-1 was a full agonist in suppressing proliferation of several human cancer cells. Microarrays demonstrated that VDRL-1 exerted a near identical expression pattern to that of 1,25-D3 in several human cancer cells. Taqman analysis of known and novel VDR-regulated genes showed that VDRL-1 was a full agonist on osteocalcin (OC), CYP24A1, and other genes. It exerted partial agonist activity on G0/G1 switch gene 2 (G0S2). Furthermore, VDRL-1 could be a full or partial agonist of calcium transporter 1 (TRPV6) expression and partially antagonized 1,25-D3 in cells where it partially regulated TRPV6. Thus, the current study describes a novel nonsecosteroidal VDR ligand that behaves mostly like 1,25-D3, but possesses unique characteristics. Drug Dev Res 68:51-60, 2007. © 2007 Wiley-Liss, Inc.