Proteolysis-targeting chimera (PROTAC) targeting bruton tyrosine kinase (BTK) degradation for cancer therapy in mantle cell lymphoma Free

Background Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma sub-type 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) facelifting BTK-degradation (BTK-PROTAC) are a potential therapy.Methods We designed several BTK-PROTACs which were screened for activity against MCL using functional in vitro assays and a mouse model. Effects of BTK-PROTACs on differentially expressed genes and on activation of the BCR-signaling cascade were identified by RNA sequencing and molecular experiments. BTK variant cells were developed to assess the ability of BTK-PROTACs to overcome acquired BTK-inhibitor resistance.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 a mouse xenograft models with BTK^C481SandBTK^L528W variants.Conclusion The C23 BTK-PROTAC inhibits MCL cells with BTK variants resistant to BTK-inhibitors in vitroand in vivo models. C23 BTK-PROTAC is a potential therapy of BTK-inhibitor resistant MCL.