2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Feb 10;65(3):2059-2077. doi: 10.1021/acs.jmedchem.1c01598.
Zhangping Xiao 1,  Angelina Osipyan 1,  Shanshan Song 1 2,  Deng Chen 1,  Reinder A Schut 1,  Ronald van Merkerk 1,  Petra E van der Wouden 1,  Robbert H Cool 1,  Wim J Quax 1,  Barbro N Melgert 2 3,  Gerrit J Poelarends 1,  Frank J Dekker 1
Affiliations

Affiliations

  • 1 Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
  • 2 Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
  • 3 University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
PMID: 35041425 DOI: 10.1021/acs.jmedchem.1c01598
Abstract

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.

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