The JAK1/2 Inhibitor Momelotinib Does Not Inhibit Thiamine Uptake in Vitro

The clinical development of a selective JAK2 inhibitor, fedratinib, was terminated due to cases of Wernicke's encephalopathy, a disease related to thiamine insufficiency. Furthermore, a recent publication reported potent inhibition of the thiamine transporter 2 (THTR2; SLC19A3) by fedratinib1. This study aimed to determine the potential for other JAK inhibitors to inhibit thiamine transport and to better elucidate the structural basis for inhibition. The effect of the aminopyrimidine containing JAK inhibitors fedratinib, AZD1480, momelotinib, and XL-019 on thiamine transport in Caco-2 cells and HEK293 cells transfected with human THTR1 (SLC19A2) and 2 was assessed. Consistent with the prior publication, fedratinib inhibited thiamine uptake in Caco-2 cells (IC50=0.94 ± 0.08 μM) and THTR2 transfected cells (IC50=1.6 ± 0.52 μM). We also observed inhibition of THTR1 by fedratinib (IC50=7.9 ± 0.97 μM). Another JAK inhibitor, AZD1480, also inhibited thiamine transport, but to a lesser degree (Caco-2, IC50=8.1 ± 0.1 μM). In contrast, momelotinib and XL-019 did not inhibit thiamine transport in any of the systems tested. A pharmacophore model derived from the minimized structure of thiamine suggests that the 2,4-diaminopyrimidine containing JAK inhibitors fedratinib and AZD1480 can adopt a conformation matching several key features of thiamine, while inhibitors lacking the 4-amino group and/or an additional hydrogen bond donor poorly align with thiamine. In summary, these results suggest that not all JAK inhibitors have the potential to inhibit thiamine transport. In particular, momelotinib, currently in Phase 3 clinical trials for the treatment of pancreatic cancer and myelofibrosis, showed no potential to affect thiamine levels.