Reprogramming VHL with molecular glues enables selective degradation of caspase-2

Hu, J.; Deng, W.; Ou, S.-C.; Golkar, A.; Inglis, A.; Smither, K.; Li, S.; Chen, K.; Cho, K.; Bae, S. J.; Zech, S.; Choi, K.; den Besten, W.; Voss, S.; Bedel, O.; Zhou, B.; Potts, P. R.; Sadok, A.; Min, J.

doi:10.64898/2026.08.12.744529

bioRxiv · 10.64898/2026.08.12.744529

Reprogramming VHL with molecular glues enables selective degradation of caspase-2

Hu, J.·Deng, W.·Ou, S.-C.·Golkar, A.·Inglis, A.·Smither, K.·Li, S.·Chen, K.·Cho, K.·Bae, S. J.·Zech, S.·Choi, K.·den Besten, W.·Voss, S.·Bedel, O.·Zhou, B.·Potts, P. R.·Sadok, A.·Min, J.

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Abstract

Molecular glue degraders (MGDs) reprogram E3 ligases to eliminate neosubstrates, yet their application has largely been confined to CRBN. Here, we identify caspase-2 as a new neosubstrate for von Hippel-Lindau (VHL), expanding the scope of VHL-based MGDs. Guided by a focused VHL ligand library design, we employed TurboID-based proximity labeling to discover stereoisomeric compounds (dCASP2-1 and dCASP2-2) that selectively recruit caspase-2 to VHL and promote its ubiquitin-proteasome system-dependent degradation. Further structure-activity relationship (SAR) studies yielded dCASP2-3 and dCASP2-4, which enhanced degradation potency (by 622-fold relative to dCASP2-1) and abolished enantioselectivity. Mechanistic mapping localized the degrader-induced interface to a two-helix region of the caspase-2 CARD domain, with residues H33, P34, and D100 essential for VHL engagement. Degron-guided computational modeling of the VHL/MGD/caspase-2 ternary complex provided structural insight into neosubstrate recognition. Together, we report the development of VHL molecular glues that selectively and potently degrade caspase-2, offering chemical probes to interrogate its functions in apoptosis and stress responses, while broadening the substrate landscape of VHL-based MGDs.

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Hu, J., Deng, W., Ou, S.-C., Golkar, A., Inglis, A., Smither, K., Li, S., Chen, K., Cho, K., Bae, S. J., Zech, S., Choi, K., den Besten, W., Voss, S., Bedel, O., Zhou, B., Potts, P. R., Sadok, A., Min, J.. 2026-08-17. Reprogramming VHL with molecular glues enables selective degradation of caspase-2. https://doi.org/10.64898/2026.08.12.744529

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