Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain.

The voltage-gated sodium channels (VGSC) NaV1.8 and NaV1.7 (NaVs) have emerged as promising and high-value targets for the development of novel, non-addictive analgesics to combat the chronic pain epidemic. In recent years, many small molecule inhibitors against these channels have been developed. The recent successful clinical trial of VX-548, a NaV1.8-selective inhibitor, has spurred much interest in expanding the arsenal of subtype-selective voltage-gated sodium channel therapeutics. Toward that end, we sought to determine whether NaVs are amenable to targeted protein degradation with small molecule degraders, namely proteolysis-targeting chimeras (PROTACs) and molecular glues. Here, we report that degron-tagged NaVs are potently and rapidly degraded by small molecule degraders harnessing the E3 ubiquitin ligases cereblon (CRBN) and Von Hippel Lindau (VHL). Using LC/MS analysis, we demonstrate that PROTAC-mediated proximity between NaV1.8 and CRBN results in ubiquitination on the 2(nd) intracellular loop, pointing toward a potential mechanism of action and demonstrating the ability of CRBN to recognize a VGSC as a neosubstrate. Our foundational findings are an important first step toward realizing the immense potential of NaV-targeting degrader analgesics to combat chronic pain.