title: The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy.
abstract: The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.
authors: Incyte Corporation, Wilmington, Delaware qizhang@incyte.com.
authors: Qiang
authors: Q
authors: Zhang
authors: Incyte Corporation, Wilmington, Delaware.
authors: Yan
authors: Y
authors: Zhang
authors: Incyte Corporation, Wilmington, Delaware.
authors: Sharon
authors: S
authors: Diamond
authors: Incyte Corporation, Wilmington, Delaware.
authors: Jason
authors: J
authors: Boer
authors: Incyte Corporation, Wilmington, Delaware.
authors: Jennifer J
authors: JJ
authors: Harris
authors: Incyte Corporation, Wilmington, Delaware.
authors: Yu
authors: Y
authors: Li
authors: Incyte Corporation, Wilmington, Delaware.
authors: Mark
authors: M
authors: Rupar
authors: Incyte Corporation, Wilmington, Delaware.
authors: Elham
authors: E
authors: Behshad
authors: Incyte Corporation, Wilmington, Delaware.
authors: Christine
authors: C
authors: Gardiner
authors: Incyte Corporation, Wilmington, Delaware.
authors: Paul
authors: P
authors: Collier
authors: Incyte Corporation, Wilmington, Delaware.
authors: Phillip
authors: P
authors: Liu
authors: Incyte Corporation, Wilmington, Delaware.
authors: Timothy
authors: T
authors: Burn
authors: Incyte Corporation, Wilmington, Delaware.
authors: Richard
authors: R
authors: Wynn
authors: Incyte Corporation, Wilmington, Delaware.
authors: Gregory
authors: G
authors: Hollis
authors: Incyte Corporation, Wilmington, Delaware.
authors: Swamy
authors: S
authors: Yeleswaram
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D013449:Sulfonamides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D013831:Thiamine / Q000378:metabolism*; D013832:Thiamine Deficiency / Q000139:chemically induced*; D014899:Wernicke Encephalopathy / Q000209:etiology* / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D053614:Janus Kinase 2; D026901:Membrane Transport Proteins; D017856:Phosphotransferases (Phosphate Group Acceptor); D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; D013831:Thiamine; C492291:SLC19A3 protein, human; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human; C022733:thiamin-diphosphate kinase