Emily Ho Rose Hills
Identifying Targets and Biological Mechanisms of Gymnastatins
Proteins are essential parts of our being, but are also at the root of many health conditions when misformed. One novel approach to treating such diseases is with molecular glues: small molecules that can cause targeted protein degradation or stabilization. My project focuses on a set of potential molecular glues known as gymnastatins, which are natural products originating from the fungal strain Gymnascella dankaliensis. The Nomura Research Group has demonstrated that gymnastatins have antiproliferative effects on breast cancer cells. Dankastatin B, the most potent gymnastatin against cancer cell viability, targets the mitochondrial membrane proteins VDAC2 and VDAC3. VDAC2 and VDAC3 were verified to be related to the proteins anticancer effects, but it is currently unknown how exactly these proteins are involved in intrinsic apoptosis (cell death). We hypothesize that dankastatin B acts as a molecular glue between VDAC2 and VDAC3, aiding in the initiation of apoptosis in cancer cells. This project aims to further decipher the mechanism of dankastatin B through shRNA knockout studies, structure-activity relationship studies, and ternary complex formation assays.
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