When inhibitors degrade – supercharging native protein turnover

Recently, sporadic reports have highlighted that chemical matter designed to inhibit a protein can sometimes also lead to its degradation. Crucially, degradation often governs their superior drug action. However, we lack an understanding of frequency, generalizability, and mechanistic underpinnings of these phenomena. To close this gap, we systematically surveyed 98 kinases against 1600 kinase inhibitors. We uncovered that inhibitor-induced degradation is a frequent event, and functions by tuning endogenous proteostatic equilibria. Hence, they mechanistically transcend proximity-based approaches leveraged by conventional degraders, and therefore outline a novel approach to pharmacologic modulation of protein abundance.