Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor

Autor: 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
Rok vydání: 2023
Předmět:
Zdroj: Blood.
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.2022018674
Popis: Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies. However, approved covalent BTK inhibitors (cBTKi) are associated with treatment limitations due to off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here we describe the preclinical profile of pirtobrutinib, a potent, highly selective, non-covalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate (ATP)-binding region and shows no direct interaction with C481. As a result, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKi, prevented Y551 phosphorylation in the activation loop. These data suggest pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. 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.
Databáze: OpenAIRE
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