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

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/TCI
system highlights the 2-sulfonylpyrimidine group as a useful acrylamide
replacement. In the future, it will be interesting to investigate
its wider potential for developing TCIs with improved pharmacologies
and selectivity profiles across structurally related protein families.