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

Nat Cancer. 2022 Feb;3(2):156-172. doi: 10.1038/s43018-022-00331-y.

Nadilly Bonagas ^# ¹, Nina M S Gustafsson ^# ¹, Martin Henriksson ^# ¹, Petra Marttila ^# ¹, Robert Gustafsson ², Elisée Wiita ¹, Sanjay Borhade ¹, Alanna C Green ³, Karl S A Vallin ¹, Antonio Sarno ⁴, Richard Svensson ⁵, Camilla Göktürk ¹, Therese Pham ¹, Ann-Sofie Jemth ¹, Olga Loseva ¹, Victoria Cookson ³, Nicole Kiweler ⁶, Lars Sandberg ⁷, Azita Rasti ¹, Judith E Unterlass ¹, Martin Haraldsson ⁸, Yasmin Andersson ⁹, Emma R Scaletti ² ¹⁰, Christoffer Bengtsson ⁷, Cynthia B J Paulin ¹, Kumar Sanjiv ¹, Eldar Abdurakhmanov ¹¹, Linda Pudelko ¹, Ben Kunz ¹, Matthieu Desroses ¹, Petar Iliev ¹, Katarina Färnegårdh ⁷, Andreas Krämer ¹², Neeraj Garg ¹³, Maurice Michel ¹, Sara Häggblad ¹⁴, Malin Jarvius ¹⁵, Christina Kalderén ¹, Amanda Bögedahl Jensen ¹, Ingrid Almlöf ¹, Stella Karsten ¹, Si Min Zhang ¹, Maria Häggblad ¹⁴, Anders Eriksson ¹⁶, Jianping Liu ¹⁶, Björn Glinghammar ⁸, Natalia Nekhotiaeva ¹⁶, Fredrik Klingegård ⁷, Tobias Koolmeister ¹, Ulf Martens ¹⁴, Sabin Llona-Minguez ¹, Ruth Moulson ¹, Helena Nordström ¹¹, Vendela Parrow ¹⁵, Leif Dahllund ⁹, Birger Sjöberg ⁸, Irene L Vargas ¹, Duy Duc Vo ¹³, Johan Wannberg ¹³, Stefan Knapp ¹², Hans E Krokan ⁴, Per I Arvidsson ⁸, Martin Scobie ¹, Johannes Meiser ⁶, Pål Stenmark ² ¹⁰, Ulrika Warpman Berglund ¹, Evert J Homan ¹, Thomas Helleday ¹⁷ ¹⁸

Affiliations

1 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
2 Department of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.
3 Weston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.
4 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
5 Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala, Sweden.
6 Cancer Metabolism Group, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
7 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
8 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
9 Drug Discovery and Development Platform, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology, Solna, Sweden.
10 Department of Experimental Medical Science, Lund University, Lund, Sweden.
11 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
12 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
13 Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
14 Biochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
15 Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
16 Karolinska High Throughput Centre, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
17 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. thomas.helleday@scilifelab.se.
18 Weston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK. thomas.helleday@scilifelab.se.
# Contributed equally.

PMID: 35228749 DOI: 10.1038/s43018-022-00331-y

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-155950

TH9619

99.33%, MTHFD2 Inhibitor

Methylenetetrahydrofolate Dehydrogenase (MTHFD); Apoptosis

Cancer
HY-155219

TH9028

MTHFD2 Inhibitor

Methylenetetrahydrofolate Dehydrogenase (MTHFD)

Cancer

Name
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