UCSF

Protein-protein interactions (PPIs) are central to biology and commonly dysregulated in disease. Despite their importance in cell homeostasis and their therapeutic potential, PPIs have rarely been a target for drug discovery. This has been due to three major challenges PPIs present to small molecule engagement: the flatness problem, the disorder problem, and the selectivity problem. PPIs which bind with large, flat interfaces typically do not have deep pockets accessible to small molecules, leading to low ligand efficiency. Intrinsically disordered proteins, likewise, are lacking in “hot spots” for small molecule binding. Finally, most proteins which participate in PPIs have more than one partner– 20% of so-called hub proteins with multiple interactions have over 20 binding partners– thus necessitating a selective small molecule to target a specific PPI edge as opposed to a general effector which inhibits the nodular hub protein. Disulfide tethering, a subset of fragment-base drug discovery (FBDD) offers a novel approach to the rapid discovery and development of potent, selective small molecule PPI modulators. This platform facilitates rapid and robust compound discovery and validation as well as simple, accessible scaffolds for hit-to-lead development, circumventing the difficulty of natural product total synthesis and mitigating costly late-stage failures in selectivity and safety. This work showcases multiple projects utilizing disulfide tethering to discover and optimize small molecule modulators for various “undruggable” targets within oncology, neurodegeneration, metabolic disease, and infectious disease.