Developing Potent and Selective TBK1 Molecular Glue Degraders for Cancer Immunotherapy

Caldwell, J. J.; Zanon, P. R. A.; Ferguson, I.; Hallett, S. T.; Tenev, T.; Aparicio, N.-S.; Wood, R. J. H.; Khan, S.; John, S. W.; Wilson, R.; Warren, M. T.; McAndrew, P. C.; Steger, M.; Winkler, D.; Ohmayer, U.; Schwalb, B.; Shashikadze, B.; Le Bihan, Y.-V.; Scarpino, A.; Mitsopoulos, K.; Dziegiel, F.; Konopacka, A.; Van Montfort, R. L. M.; Meier, P.; Daub, H.; Rankovic, Z.

doi:10.64898/2026.01.30.702304

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bioRxiv · 10.64898/2026.01.30.702304

Developing Potent and Selective TBK1 Molecular Glue Degraders for Cancer Immunotherapy

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Abstract

Immune checkpoint blockade (ICB) has transformed cancer therapy across multiple tumour types, yet primary and acquired resistance remain major barriers to durable benefit. TANK-binding kinase 1 (TBK1) has emerged as an attractive target to enhance anti-tumour immunity, acting as a serine/threonine kinase that restrains immunogenic cell death and downstream immune activation. Here we report the discovery of a first-in-class TBK1 molecular glue degrader (MGD), CCT412020, identified through high-throughput proteomics screening of a next-generation molecular glue library. CCT412020 induces rapid, potent and selective TBK1 degradation across a panel of breast cancer cell lines. A cryo-EM structure of CCT412020 in complex with CRBN/{Delta}BPB-DDB1 and TBK1-homodimer reveals an unexpected binding mode that bypasses the canonical G-loop and instead engages an unconventional site at the TBK1 homodimer interface. Functionally, TBK1 loss via CCT412020 sensitises tumour cells to TNF- and interferon-driven responses and reduced viability across a broad range of cancer cell lines. Together, these findings establish CCT412020 as a mechanistically distinct TBK1 degrader and provide a framework for developing TBK1-targeted degraders as immunomodulatory anti-cancer agents to overcome ICB resistance.

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Caldwell, J. J., Zanon, P. R. A., Ferguson, I., Hallett, S. T., Tenev, T., Aparicio, N.-S., Wood, R. J. H., Khan, S., John, S. W., Wilson, R., Warren, M. T., McAndrew, P. C., Steger, M., Winkler, D., Ohmayer, U., Schwalb, B., Shashikadze, B., Le Bihan, Y.-V., Scarpino, A., Mitsopoulos, K., Dziegiel, F., Konopacka, A., Van Montfort, R. L. M., Meier, P., Daub, H., Rankovic, Z.. 2026-02-02. Developing Potent and Selective TBK1 Molecular Glue Degraders for Cancer Immunotherapy. https://doi.org/10.64898/2026.01.30.702304

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