Tuesday, August 13, 2024

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

Ruxandra Moraru, Beatriz Valle-Argos, Annabel Minton, Lara Buermann, Suyin Pan, Thomas E. Wales, Raji E. Joseph, Amy H. Andreotti, Jonathan C. Strefford, Graham Packham, and Matthias G. J. Baud

Journal of Medicinal Chemistry 2024

DOI: 10.1021/acs.jmedchem.3c01927

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.


Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling

Lukas Bissegger,  Theodora A. Constantin,  Erhan Keles,  Luka Raguž,   Isobel Barlow-Busch,  Clara Orbegozo,   Thorsten Schaefer,  Valentina...