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Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor
Research Article | Eliana B Gomez, Kevin Ebata, Hetal S Randeria, Mary S Rosendahl, Ernst Peder Cedervall, Tony H Morales, Lauren M Hanson, Nicholas E Brown, Xueqian Gong, Jennifer Rachelle Stephens, Wenjuan Wu, Isabel Lippincott, Karin S. Ku, Richard A Walgren, Paolo B Abada, Joshua A Ballard, Charles K Allerston, Barbara J Brandhuber; Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor.
Conclusions: Pirtobrutinib is efficacious in B-cell models in vitro and in vivo, including patient derived CLL cells.
• Source: Blood
• Conclusions/Relevance: “Collectively, these findings suggest pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical and structural attributes with the potential to treat B-cell driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.”
• Currently approved covalent BTK inhibitors (cBTKi) are related to treatment limitations due to off-target adverse effects, suboptimal oral pharmacology, and the development of resistance mutations (eg, C481) that prevent inhibitor binding.
• Pirtobrutinib is a potent, non-covalent (i.e., reversible), highly selective inhibitor of BTK and C481-mutant BTK that is effective in in vitro and in vivo models, including patient derived CLL cells.
• Pirtobrutinib binds BTK via an extensive network of interactions to BTK and water molecules at the level of the adenosine triphosphate (ATP)-binding region. Pirtrobrutinib does not interact with C481, thus blocking both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays via similar potencies.