Exploring 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition: A BTK Story.

ABSTRACT: Targeted covalent inhibitors (TCIs) directing cysteine have historically relied on a narrow set of electrophilic "warheads". While Michael acceptors remain at the forefront of TCI design strategies, they show variable stability and selectivity under physiological conditions. Here, we show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib, for the inhibition of Bruton's tyrosine kinase. In a few iterations, we discovered new derivatives, which inhibit BTK both in vitro and in cellulo at low nanomolar concentrations, on par with Ibrutinib. Several derivatives also displayed good plasma stability and reduced off-target binding in vitro across 135 tyrosine kinases. This proof-of-concept study on a well-studied kinase/TC

SUBMITTER: Moraru R 

PROVIDER: S-EPMC11345841 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature