Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy

Sci Transl Med. 2018 Feb 14;10(428):eaaf7444. doi: 10.1126/scitranslmed.aaf7444.

William C Stafford ¹ ², Xiaoxiao Peng ¹, Maria Hägg Olofsson ³, Xiaonan Zhang ³, Diane K Luci ⁴, Li Lu ⁵, Qing Cheng ¹, Lionel Trésaugues ⁶, Thomas S Dexheimer ⁴, Nathan P Coussens ⁴, Martin Augsten ³, Hanna-Stina Martinsson Ahlzén ¹, Owe Orwar ² ⁷, Arne Östman ³ ⁸, Sharon Stone-Elander ⁹ ¹⁰, David J Maloney ⁴, Ajit Jadhav ⁴, Anton Simeonov ⁴, Stig Linder ³ ¹¹, Elias S J Arnér ¹²

Affiliations

1 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
2 Oblique Therapeutics AB, SE 413 46 Gothenburg, Sweden.
3 Department of Oncology-Pathology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
4 NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-4874, USA.
5 Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, SE 171 76 Stockholm, Sweden.
6 Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
7 Department of Physiology and Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
8 University of Bergen, Postboks 7804, N-5020 Bergen, Norway.
9 Department of Neuroradiology, Positron Emission Tomography Radiochemistry, Karolinska University Hospital, SE 171 76 Stockholm, Sweden.
10 Department of Clinical Neurosciences, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
11 Division of Drug Research, Department of Medicine and Health, Linköping University, SE 581 83 Linköping, Sweden.
12 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden. elias.arner@ki.se.

PMID: 29444979 DOI: 10.1126/scitranslmed.aaf7444

Abstract

Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills Cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing Enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial Enzyme TXNRD2 and additional targets. For our lead compounds, TXNRD1 inhibition correlated with Cancer cell cytotoxicity, and inhibitor-triggered conversion of TXNRD1 from an antioxidant to a pro-oxidant Enzyme correlated with corresponding increases in cellular production of H₂O₂ In mice, the most specific TXNRD1 inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1), impaired growth and viability of human tumor xenografts and syngeneic mouse tumors while having little mitochondrial toxicity and being better tolerated than auranofin. These results display the therapeutic Anticancer potential of irreversibly targeting cytosolic TXNRD1 using small molecules and present potent and selective TXNRD1 inhibitors. Given the pronounced up-regulation of TXNRD1 in several metastatic malignancies, it seems worthwhile to further explore the potential benefit of specific irreversible TXNRD1 inhibitors for Anticancer therapy.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-125006

TRi-1

99.91%, TXNRD1 Inhibitor

Others

Cancer

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