fedratinib and 2-4-diaminopyrimidine

Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke's encephalopathy and subsequent termination of clinical development of fedratinib, a Janus kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using human epithelial colorectal adenocarcinoma (Caco-2) and thiamine transporter (THTR) overexpressing cells and to better elucidate the structural basis for interacting with THTR. Only JAKi containing a 2,4-diaminopyrimidine were observed to inhibit thiamine transporters. Fedratinib inhibited thiamine uptake into Caco-2 cells (IC

Topics: Caco-2 Cells; Drug Interactions; HEK293 Cells; Humans; Janus Kinase Inhibitors; Membrane Transport Proteins; Molecular Structure; Pyrimidines; Pyrrolidines; Substrate Specificity; Sulfonamides; Thiamine; Trimethoprim