Disrupting linearity of PROTAC scaffolds prevents off-target complex I inhibition
Nick Richert, Hana Nůsková, Jana Samarin, Bozhidar S. Ivanov, Mohamad Saoud, Frank H. Deis, Nicole de Vries, Sonja Sievers, Gernot Poschet, Slava Ziegler, Judy Hirst, Nikolas Gunkel, Aubry K. Miller
The paper identifies that linear PROTAC scaffolds inhibit mitochondrial complex I, leading to ATP depletion, and proposes structural modifications to mitigate this off-target effect.
bioRxiv · Apr 24, 2026 · PreprintCancer Biology