Thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione Derivative Inhibits d -Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells

Zhangping Xiao, Angelina Osipyan, Shanshan Song, Deng Chen, Reinder A Schut, Ronald van Merkerk, Petra E van der Wouden, Robbert H Cool, Wim J Quax, Barbro N Melgert, Gerrit J Poelarends, Frank J Dekker*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The homologous cytokines macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT or MIF2) play key roles in cancers. Molecules binding to the MIF tautomerase active site interfere with its biological activity. In contrast, the lack of potent MIF2 inhibitors hinders the exploration of MIF2 as a drug target. In this work, screening of a focused compound collection enabled the identification of a MIF2 tautomerase inhibitor R110. Subsequent optimization provided inhibitor 5d with an IC50 of 1.0 μM for MIF2 tautomerase activity and a high selectivity over MIF. 5d suppressed the proliferation of non-small cell lung cancer cells in two-dimensional (2D) and three-dimensional (3D) cell cultures, which can be explained by the induction of cell cycle arrest via deactivation of the mitogen-activated protein kinase (MAPK) pathway. Thus, we discovered and characterized MIF2 inhibitors (5d) with improved antiproliferative activity in cellular models systems, which indicates the potential of targeting MIF2 in cancer treatment.

Original languageEnglish
Pages (from-to)2059-2077
JournalJournal of Medicinal Chemistry
Issue number3
Early online date18-Jan-2022
Publication statusPublished - 10-Feb-2022

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