What is it about?
Commenting on the published characterization of the reversible BTK inhibitor XMU-MP-3, we discuss how cell line models, including those expressing mutant BTK, can be advantageously employed for the pre-clinical assessment of drug candidates against B cell malignancies.
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Why is it important?
In response to a wealth of experimental data presented by Gui et al. (20219), we share three major lines of thought regarding their interpretation. (1) Functions of BTK as such are fundamentally different from those of strongly oncogenic TEL-BTK fusion proteins. This means for instance that the unnaturally high oncogenicity of TEL-BTK fusion proteins precludes their use as chemical genetic probes of physiological BTK function. (2) Because cysteine 481 is involved in the interaction of the BTK binding pocket with irreversible, but not with reversible inhibitors, the latter are typically not affected by the C481S resistance mutation, as observed here with XMU-MP-3, but also previously e.g. with dasatinib. (3) There is ample opportunity for relevant inhibitor assessment using appropriate cell line models not only of malignant B cells but also of bystander cells from the tumor microenvironment.
Perspectives
Well-considered cell line-based research, including parallel approaches with isogenic cell lines, enables contributions to pre-clinical drug assessment that range from substitutes of biochemical inhibitor potency assays to the analysis of tumor microenvironment interactions.
Dr Günter Krause
University of Cologne
Read the Original
This page is a summary of: Cell line‐based assessment of BTK inhibitors, British Journal of Pharmacology, January 2020, Wiley,
DOI: 10.1111/bph.14948.
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