Micah Fernando

I work on developing and characterizing small molecule Rab GTPase probes. I leverage chemical genetics by introducing a nucleophilic cysteine equivalent to KRas G12C that allows covalent modification of the allosteric switch II pocket.

The vast majority of the human proteome is still undrugged. Even with the advent of protein-ligand structure prediction models such as AlphaFold3, developing selective small- molecule probes remains a significant challenge. Rab GTPases are one such family of proteins lacking effective probes, with previous attempts suffering from poor potency and selectivity. Rab GTPases are crucial regulators of vesicle trafficking and organelle biogenesis within the cell. My project involves using a chemical genetics approach to inhibit Rab GTPases. Inhibition of the oncogenic mutant GTPase KRas G12C was pioneered in our lab by identifying small molecules that covalently engage the mutant cysteine and bind to an allosteric pocket. While in the Shokat group, I have helped determine the conservation of this pocket in other GTPases, including the Rab family. This chemical genetic approach involves introducing a nucleophilic cysteine at the KRAS equivalent position in the GTPase of interest to confer covalent inhibitor sensitivity, so that its function can be interrupted at rapid time points.