Proteolysis-targeting chimera (PROTAC) to target Bruton tyrosine kinase (BTK) degradation in mantle cell lymphoma.

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Background: Mantle cell lymphoma (MCL) is characterized by Bruton tyrosine kinase (BTK)-signaling which activates the B-cell receptor (BCR) signaling cascade. Although BTK-inhibitors are effective therapy, acquired resistance is common. Proteolysis-targeting chimera molecules (PROTACs) facilitating BTK-degradation (BTK-PROTAC) are a potential therapy. Methods: We designed 24 BTK-PROTACs and screened their activity against MCL cell lines through half maximal inhibitory concentration (IC50) assays and BTK-degradation efficiency. Effects of BTK-PROTAC on differentially expressed genes and on activation of the BCR-signaling cascade were studied by RNA-seq and molecular experiments. BTK variant cells were developed to assess the ability of BTK-PROTAC to reverse acquired BTK-inhibitor resistance in vitro assays and in mouse models. Results: Amongst BTK-PROTACs we synthesized C23 had the strongest ability to degrade BTK and inhibit proliferation of several MCL cell lines. C23 induced cell apoptosis and suppressed cancer growth by activating the ubiquitin-proteasome pathway thereby inhibiting the BCR-signaling cascade including NF-κB- and PI3K-AKT-mTOR-signaling. C23 degraded BTK inhibiting growth of BTK ^C481S and BTK ^L528W variant cells and suppressed growth of MCL cells in mouse xenograft models with BTK ^C481S and BTK ^L528W variants. Conclusions: The C23 BTK-PROTAC inhibits MCL cells with BTK variants resistant to BTK-inhibitors in vitro and in vivo models. BTK-PROTAC C23 is a potential therapy of BTK-inhibitor resistant MCL.