One area of research in the Shair group is the synthesis of complex molecules that exhibit interesting biological properties. We are developing syntheses that are efficient enough to provide material for our own studies of the biological properties of these compounds. These syntheses have required innovative solutions such as novel transformations or complexity-generating reactions and strategies.
Recently, we completed syntheses of cortistatin A, cephalostatin 1, and fastigiatine. Complexity generating cascade reactions figured prominently into these syntheses. We are currently focused on syntheses of the lomaiviticins, hyperforin, and angelmicin B.
We explore the biological activities of the small molecules made in our lab. For instance, we used affinity chromatography and quantitative proteomics to reveal that oxysterol binding protein (OSBP) and its paralog OSBP-related protein 4L (ORP4L) are high affinity targets of the antiproliferative natural products cephalostatin 1, OSW-1, schweinfurthin A, and ritterazine B. We have now named this mechanistically related family of small molecules ORPphilins. We then used chemical, genetic, and biochemical approaches to confirm that OSBP and ORP4L mediate the antiproliferative activities of ORPphilins. These studies were the first to show that cancer cell survival is highly dependent on OSBP and ORP4L. We are using ORPphilins to study the poorly understood function of OSBP and ORP4L in cells and animals. We are also studying the therapeutic potential of ORPphilins.
Other compounds prepared in the Shair lab are the subject of studies to understand their cellular target and mechanism in cells. Often, these studies reveal new aspects of cell biology and in some cases, druggable targets for the treatment of human diseases.