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. 2023 Jul 25;7(14):3378-3381.
doi: 10.1182/bloodadvances.2022009366.

BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib

Ross A Jackson  1 , Robert G Britton  2   3 , Sandrine Jayne  1 , Susann Lehmann  4 , Caroline M Cowley  5 , Christopher S Trethewey  1 , Victoria M Smith  1 , Ralf Schmid  6 , Christopher Fegan  7 , Harriet S Walter  1 , Martin J S Dyer  1
Affiliations

BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib

Ross A Jackson et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: S.J., H.S.W., and M.J.S.D. have received research funding from Gilead Sciences. H.S.W. and M.J.S.D. have received research funding from BeiGene and Loxo Oncology. The remaining authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
BTK mutations in patients with CLL receiving tirabrutinib. (A) Schematic domain structure of BTK with mutations identified in this study (top) (with each arrow denoting a single patient) and mutations identified in other studies of patients treated with ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib (bottom). (B) Molecular modeling of the BTK pleckstrin homology (PH)-domain E108K mutation. Ins(1,3,4,5)P4 are shown as spheres, PH-domain residues of interest are shown as sticks. The β1-β2 loop, which forms part of the Ins(1,3,4,5)P4 binding site is indicated in green. (Left) E108 and K16 form a salt bridge, which stabilizes the Ins(1,3,4,5)P4 binding site. (Right) the E108K mutation interrupts the salt bridge to K16 and is likely to destabilize the Ins(1,3,4,5)P4 binding site because of electrostatic repulsion via K16 of the β1-β2 loop. (C-D) Molecular modeling of ibrutinib (pale green), tirabrutinib (yellow), and zanubrutinib (purple) bound to BTK. BTK W528 disrupts the binding of BTKi to BTK, with additional steric clash observed with tirabrutinib and zanubrutinib (denoted by red dotted lines). Mutated W528 is shown in bright green, and T474 shown in orange.
See this image and copyright information in PMC

References

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