More than an attachment module: covalent inhibitor warheads influence BTK dynamics and function

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ABSTRACT Covalent inhibitors are rapidly becoming the standard of care for treatment of a range of disease states. Covalent inhibitors bind irreversibly to their target using a reactive electrophile (or ‘warhead’). Acrylamide and 2-butynamide are the most commonly used cysteine targeting electrophiles. These warheads are chosen for their efficient and selective modification of the protein and are presumed to be otherwise functionally inert. Using a panel of BTK covalent inhibitors (Tirabrutinib, Acalabrutinib, Ibrutinib and Zanubrutinib), we show that the 2-butynamide warhead on Tirabrutinib and Acalabrutinib, unlike the acrylamide warhead on Ibrutinib and Zanubrutinib, induces conformational heterogeneity in key regions required for BTK signaling. Tirabrutinib or Acalabrutinib bound BTK adopt multiple conformational states that are in dynamic exchange, show increased binding to the substrate PLCγ and are less effective at inhibiting PLCγ signaling when compared to Ibrutinib. Swapping only the warheads between Tirabrutinib and Ibrutinib leads to a corresponding switch in BTK dynamics and inhibitor efficacy. The unanticipated warhead-specific allosteric effects raise interesting possibilities regarding inhibitor-specific mechanisms of resistance. SIGNIFICANCE STATEMENT Treatment of B-cell cancers such as Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma has been revolutionized by the development of covalent inhibitors that target Bruton’s Tyrosine Kinase (BTK). These orally bioavailable cancer drugs are highly effective in interfering with B-cell growth and provide patients with long lasting remission. These treatments do come with vulnerabilities as inhibitor-specific resistance mutations emerge in a subset of patients. Here we investigate how chemical differences among available BTK inhibitors drive differential protein dynamics and signaling interactions that could foreshadow specific resistance mechanisms. As continuous use of BTK inhibitors progresses in time, the field will continue to learn which drugs, and which structural features of these drugs, either limit resistance or provide alternatives to established resistance.

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