Oxysterol Small Molecules

Oxysterols comprise a family of oxygenated derivatives of cholesterol that are present in the circulation, and in human and animal tissues. A role for specific oxysterols has been implicated in various physiologic processes including cholesterol metabolism, cellular differentiation, inflammation, apoptosis, and steroid production. The main identified receptors for certain oxysterols that upon activation result in regulation of the transcription of target genes are the liver X receptors (LXRs). However, many of the effects of oxysterols are not entirely explained by LXR activation, including their osteoinductive and anti-adipogenic effects on mesenchymal cells. We recently showed that these effects of specific oxysterols are mediated mainly through the activation of Hedgehog (Hh) signaling, a novel and previously unrecognized finding. Moreover, we reported that osteogenic oxysterols synergize with bone morphogenetic proteins (BMPs) in inducing osteogenesis in vitro. In preclinical studies we found that osteogenic oxysterols robustly stimulate new bone formation and spinal fusion in experimental animals.

Furthermore, we demonstrated that a different class of oxysterols that differ in molecular structure from the osteogenic oxysterols and activate LXR signaling act as potent inhibitors of Hh signaling and clonogenic growth of various cancer cells in vitro and in vivo. In addition, these small molecules inhibit the response of stromal cells to Hh proteins derived from tumor cells in vitro. Non-steroidal pharmacologic activators of LXR signaling upon systemic administration cause increased lipogenesis and fat deposition in the liver due to increased expression and activation of SREBP1c gene in hepatocytes. However, in contrast oxysterols, including our small molecule oxysterol-based LXR agonists, do not cause such increased lipogenesis in the liver due to their inherent ability to inhibit SREBP1c protein processing and activation. In addition, unlike Smoothened antagonists (inhibitors of Hh signaling developed by other biotech/pharmaceutical companies), oxysterols inhibit aberrant Hh signaling induced downstream of Smoothened and may therefore be effective against a greater number of Hh pathway-mediated cancers. Moreover, in more recent in vitro preclinical studies we have found that unlike resistance to chemotherapeutic agents that develops in many tumor and stromal cells after prolonged treatments, such resistance does not develop upon long term exposure of stromal cells to oxysterol LXR agonists.

The unique characteristics and advantages of oxysterols, as well as their potential for local and systemic delivery, relatively inexpensive large-scale synthesis, and anticipated lack of immunogenicity prompted us to undertake their further development into future therapeutic agents for use in targeting a variety of human diseases including cancers, bone defects, and osteoporosis. Accordingly, we have studied and continue to study structure-activity relationships for oxysterols; as a result of proprietary knowledge that we have gained, we have been able to synthesize novel small molecule oxysterols with significantly improved profiles compared to their naturally occurring counterparts and we continue to generate a pipeline of small molecule oxysterols for future development into therapeutic agents.