RNA-Seq to Explore 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition of BTK in Diffuse Large B Cell (DLBCL) Cell Line TMD8

Bruton Tyrosine Kinase (BTK) plays an essential role in signal transduction downstream of cell surface receptors on B lymphocytes, including the B-cell receptor (BCR), a key driver of several sub-types of human B-cell lymphoma and leukaemia. As such, BTK inhibitors have proven to be effective therapies for B-cell malignancies, most notably Ibrutinib. Targeted covalent inhibitors (TCIs) directing cysteine typically rely on a narrow set of electrophilic “warheads”. Michael acceptors remain at the forefront of TCI design strategies, yet have variable stability and selectivity under physiological conditions. Our RNA-Seq experiments were performed on TMD8 cells that had been cultured for 8 hours with DMSO, ibrutinib or 4 chemical constructs that we describe in Moraru et al. (2024), resulting in a total of 18 libraries. Our data show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib.