Dynamin drug development: On- and off-target modulators

Dynamins are multi-domain GTPase enzymes capable of performing the final scission of invaginated plasma membrane prior to the completion of endocytosis (as a helical oligomer) as well as functioning as a scaffolding protein in actin dynamics (as a ring oligomer). Pharmacological targeting of dynamin in mouse models provides therapeutic relief for diseases as diverse as epilepsy, cancer, and viral entry (via inhibition of helical dynamin and endocytosis) and chronic kidney disease (via stimulation of ring dynamin and actin dynamics). This thesis aims to understand the mechanisms behind the two different actions and improve targeting of dynamin for drug development by: 1) establishing the binding site of a related family of compounds (dyngo/ryngo) capable of both actions, 2) using molecular model-driven chemical modification of these compounds to generate new leads and provide insights into their in-cell action, 3) establishing carbazole-based compounds as a novel scaffold for dynamin modulation and endocytosis inhibition, and 4) demonstrating the capacity of clinically used protein kinase inhibitors to be re-purposed as either dynamin and/or endocytosis inhibitors. The overall data establishes Hinge 1 in dynamin as a novel allosteric binding site for the dyngo/ryngo family of compounds, provides significant insight into the binding mechanism, and identifies novel lead compounds that could accelerate translation of the findings into future clinical trials in humans