Discovery Biology

Since its inception 24 years ago, our lab has engaged in various multidisciplinary discovery biology projects. For example, in collaboration with the Brown/Goldstein lab, we developed small molecule analogs and chemical probes of U18666A and itraconazole that aid in understanding the mechanism of cholesterol egress from lysosomes. U18666A, a cationic amphiphilic derivative of androstenolone, and itraconazole, an antifungal agent, were shown to inhibit the exit of LDL-derived cholesterol from lysosomes and thus represent powerful tools for the study of lysosomal cholesterol transport.

Using our medicinal chemistry skills, our lab has prepared derivatives and photoaffinity-based probes useful for dissecting SAR and characterization of U18666A/itraconazole binding proteins, one of which was characterized as NPC-1. These results were published in eLife and PNAS.

More recently, our lab joined forces with the Nijhawan lab to establish a multi-pronged platform for a more efficient de-orphanization of small molecules with interesting phenotypes and unknown molecular target. We use both biochemical and forward genetics tools to achieve this.