Colin Flynn

RAS and Rho family GTPases act as molecular switches that regulate cell proliferation, cytoskeletal organization, and migration through tightly controlled cycles of activation and inactivation. These cycles are coordinated by regulatory proteins such as GEFs, GAPs, and effectors, which guide downstream signaling events. Dysregulation of these pathways is common in cancer and immune-related diseases, but direct targeting of GTPases has been limited due to their high affinity for GTP/GDP and lack of deep binding pockets. My research focuses on using fragment-based drug design (FBDD) to identify covalent and non-covalent small molecules that modulate GTPase activity or disrupt their interactions with accessory proteins. Covalent fragments target reactive residues, such as cysteines, while non-covalent fragments offer reversible control of function. I use biochemical, biophysical, and structural methods to screen and validate fragment hits, with the goal of developing chemical probes to better understand GTPase signaling dynamics. These probes will serve as tools to map key protein–protein interactions and identify druggable pockets within RAS and Rho signaling pathways, ultimately supporting efforts to target GTPase-driven processes in disease.