ArticlebioRxiv : the preprint server for biology2025
Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
5 authors.
Funding
Abstract
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
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