
This research paper investigates the distinct conformational changes induced by clinically approved BTK inhibitors on full-length BTK and elucidates the mechanisms of action of BTK resistance mutations, particularly T474I and L528W, in chronic lymphocytic leukemia.


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Inhibition of Bruton’s tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020, <https://doi.org/10.7554/eLife.60470>). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.

### Competing Interest Statement

The authors have declared no competing interest.

*   ### Abbreviations
    
    BTKi
    :   BTK inhibitor
    LKD
    :   linker-kinase domain
    CLL
    :   chronic lymphocytic leukemia
    MCL
    :   Mantle cell lymphoma
    MZL
    :   Marginal zone lymphoma
    PRR
    :   proline-rich region
    HDX-MS
    :   hydrogen/deuterium exchange-mass spectrometry
    NMR
    :   Nuclear Magnetic Resonance
    WT
    :   wild-type.

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia

conformational-effects-of-clinically-approved-btk-inhibitors-and-mechanisms-of-btk-resistance-mutations-in-chronic-lymphocytic-leukemia


Conformational Effects of Clinically Approved BTK Inhibitors and Mechanisms of BTK Resistance Mutations in Chronic Lymphocytic Leukemia
