Interaction of 2,4-Diaminopyrimidine-Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters.
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 (IC50= 0.940 µM) and THTR-2 (IC50= 1.36 µM) and, to a lesser extent, THTR-1 (IC50= 7.10 µM) overexpressing cells. Two other JAKi containing this moiety, AZD1480 and cerdulatinib, were weaker inhibitors of the thiamine transporters. Other JAKi-including monoaminopyrimidines, such as momelotinib, and nonaminopyrimidines, such as filgotinib-did not have any inhibitory effects on thiamine transport. A pharmacophore model derived from the minimized structure of thiamine suggests that 2,4-diaminopyrimidine-containing compounds can adopt a conformation matching several key features of thiamine. Further studies with drugs containing a 2,4-diaminopyrimidine resulted in the discovery that the antibiotic trimethoprim also potently inhibits thiamine uptake mediated by THTR-1 (IC50= 6.84 µM) and THTR-2 (IC50= 5.56 µM). Fedratinib and trimethoprim were also found to be substrates for THTR, a finding with important implications for their disposition in the body. In summary, our results show that not all JAKi have the potential to inhibit thiamine transport and further establish the interaction of these transporters with xenobiotics.
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.) Marilyn.Giacomini@gilead.com.
Marilyn M
MM
Giacomini
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Jia
J
Hao
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Xiaomin
X
Liang
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Jayaraman
J
Chandrasekhar
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Jolyn
J
Twelves
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
J Andrew
JA
Whitney
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Eve-Irene
EI
Lepist
Drug Metabolism Department, Gilead Sciences, Inc., (primary laboratory of origin) (M.M.G., J.H., J.T., E.-I.L., A.S.R.), Biology Department (J.A.W.), and Structural Chemistry Department (J.C.), Gilead Sciences, Inc., Foster City, California; and Department of Biopharmaceutical Sciences and Therapeutics, University of California, San Francisco, California (X.L.).
Adrian S
AS
Ray
D018938:Caco-2 Cells; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D000075242:Janus Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013831:Thiamine / Q000378:metabolism; D014295:Trimethoprim / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000075242:Janus Kinase Inhibitors; D026901:Membrane Transport Proteins; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; D013831:Thiamine; D014295:Trimethoprim; C120043:SLC19A2 protein, human; C492291:SLC19A3 protein, human; C017205:2,4-diaminopyrimidine; C528327:fedratinib; D000096926:Benzenesulfonamides