Pulz, Robert, Angst, Daniela and Cenni, Bruno (2025) Next generation Bruton's tyrosine kinase inhibitors – characterization of in vitro potency and selectivity. European journal of pharmacology, 1002. ISSN 00142999

Abstract

Bruton's tyrosine kinase (BTK) mediates B cell receptor and Fc receptor signaling and is a key regulator of autoimmunity and allergy. A series of novel BTK inhibitors (BTKi) are currently in development for non-oncologic indications with covalent-irreversible (remibrutinib, evobrutinib, tolebrutinib, orelabrutinib), covalent-reversible (rilzabrutinib), and non-covalent reversible (fenebrutinib) binding modes. This study characterizes their in vitro potency and selectivity profiles under the same conditions to minimize assay differences across the different binding modes.

The covalent BTKi showed human in vitro blood BTK binding in a time- and concentration-dependent manner with remibrutinib being the most potent and fastest in onset of action. Cellular BTK pathway inhibition was determined in human blood B cells and basophils, and for covalent BTKi correlated well with BTK binding. In contrast to the covalent-irreversible remibrutinib, the non-covalent reversible fenebrutinib showed rapid loss of cellular BTK inhibition after washout. Kinase selectivity was assessed in a binding screen across the human kinome and followed by quantification of binding affinities for a selection of kinases. The BTKi ranked in their selectivity (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions

Item Type:	Article
Date Deposited:	22 Jul 2025 00:45
Last Modified:	22 Jul 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55911