Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

Maria Häggblad, Sabin Llona-Minguez, Ulf Martens, Tobias Koolmeister, Fredrik Klingegård, Natalia Nekhotiaeva, Björn Glinghammar, Jianping Liu, Anders Eriksson, Ruth Moulson, Si Min Zhang, Stella Karsten, Ingrid Almlöf, Amanda Bögedahl Jensen, Christina Kalderén, Malin Jarvius, Sara Häggblad, Stefan Knapp, Thomas Helleday, Evert J Homan, Ulrika Warpman Berglund, Pål Stenmark, Johannes Meiser, Martin Scobie, Per I Arvidsson, Hans E Krokan, Maurice Michel, Johan Wannberg, Duy Duc Vo, Irene L Vargas, Birger Sjöberg, Leif Dahllund, Vendela Parrow, Helena Nordström, Karl S A Vallin, Nicole Kiweler, Victoria Cookson, Olga Loseva, Ann-Sofie Jemth, Therese Pham, Camilla Göktürk, Richard Svensson, Antonio Sarno, Lars Sandberg, Alanna C Green, Sanjay Borhade, Elisée Wiita, Robert Gustafsson, Petra Marttila, Martin Henriksson, Nina M S Gustafsson, Kumar Sanjiv, Neeraj Garg, Andreas Krämer, Katarina Färnegårdh, Petar Iliev, Matthieu Desroses, Ben Kunz, Linda Pudelko, Eldar Abdurakhmanov, Nadilly Bonagas, Cynthia B J Paulin, Christoffer Bengtsson, Emma R Scaletti, Yasmin Andersson, Martin Haraldsson, Judith E Unterlass, Azita Rasti

Journal: Nature cancer 2022;3(2):156-172

PMID: 35228749

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Abstract

["The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase\/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.",{"copyright":"\u00a9 2022. The Author(s)."}]

Address: Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.; Department of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.; Weston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala, Sweden.; Cancer Metabolism Group, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.; Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.; Drug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.; Drug Discovery and Development Platform, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology, Solna, Sweden.; Department of Experimental Medical Science, Lund University, Lund, Sweden.; Drug Discovery and Development Platform, Science for Life Laboratory, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.; Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.; Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Biochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.; Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.; Karolinska High Throughput Centre, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. [email protected].; Weston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK. [email protected].

DOI: 10.1038/s43018-022-00331-y

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MeSH Terms: Aminohydrolases, Humans, Hydrolases, Leukemia, Myeloid, Acute, Methylenetetrahydrofolate Dehydrogenase (NADP), Multifunctional Enzymes, Thymidine