Vitamin D3 Analogues as Hedgehog Pathway Inhibitors

     The last ten years have seen a marked increase in research aimed at the potential preventative and therapeutic anti-cancer effects of vitamin D. Much of this interest has focused on 1α,25-dihydroxyvitamin D3 (calcitriol), generally acknowledged as the hormonally active form of vitamin D. These effects are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that acts as a transcription factor to regulate apoptosis, proliferation, and differentiation. However, the clinical usefulness of calcitriol and analogues has been limited by its tendency to promote hypercalcemia, an effect related to its VDR-mediated role in calcium regulation.

     Recent studies have demonstrated that vitamin D3, a metabolic precursor to calcitriol, inhibits the hedgehog signaling pathway by direct binding to smoothened, a key regulatory protein in the hedgehog signal cascade. Inhibition of this pathway represents an exciting new intervention strategy toward the development of cancer chemotherapeutics due to its integral role in the development of skin and brain cancers. The development of vitamin D3 analogues rationally designed to exert their anti-cancer effects through inhibition of hedgehog signaling would be less susceptible to the detrimental side-effects associated with calcitriol and represent an improved class of vitamin D-based anti-cancer chemotherapeutics.

The Hadden lab is actively pursuing the following classes of Vitamin D3 analogues as novel inhibitors of Hh signaling, with structural examples shown below:

1. Vitamin D3 analogues that incorporate an aromatic A-ring mimic.

2. Side-chain analogues of vitamin D3.

3. C-ring analogues of vitamin D3.

4. Second and third generations hybrid analogues of vitamin D3.