The emerging target MTHFD2 unlocked by the Helleday lab

Inhibition of MTHFD2 – Interference in the one carbon metabolism

Inhibiting DNA repair has long been known as an effective strategy to kill cancer cells. Unfortunately, off-target effects of this type of drugs often causes toxicity even in healthy cells, which leads to suffering for the patient and can be the limiting factor for effective treatment. Through an enormous research collaboration between 5 Swedish universities, SciLifeLab and 4 other European countries and led by Karolinska Institutet, a completely new treatment and drug candidate has been developed. The drug candidate (TH9619) knocks out the MTHFD2 protein, which dividing, such as embryogenic and cancerous, cells need to survive. More specifically, certain types of blood cancer cells are sensitive to TH9619, while healthy cells are largely unaffected. We develop compounds of the series of TH9619 as a potent anti-cancer drug with minor side effects. Therefore we take TH9619 further through safety studies and then test in cancer patients.

For more information about the mechanism of action please refer to the original publication.

The Helledaylab is also open for collaborations and partnership to enable development of MTHFD2 inhibitors as potential treatments. Please contact Thomas Helleday directly for further information.

The one carbon metabolic enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer. However, its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. Recently, we have demonstrated a role for MTHFD2 in DNA replication and genomic stability in cancer cells. We developed potent and selective nanomolar MTHFD2 inhibitors. MTHFD2 inhibitors reduce replication fork speed and induce replication stress. This is followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo. The therapeutic window spans four orders of magnitude lower compared with non-tumorigenic cells. Mechanistically, MTHFD2 inhibitors prevent thymidine production leading to misincorporation of uracil into DNA and replication stress. 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.

We thank the members of the Helleday lab for fruitful discussions, the Science for Life Laboratory Drug Discovery and Development Platform, and the European Lead Factory, for their excellent service and support. The European Lead Factory has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115489, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. We thank the scientists at the Diamond Light Source (UK) and PXI of the Swiss Light Source (Switzerland) for their support during X-ray data collections. This project has received funding from Karolinska Institute’s KID funding for doctoral students (to N.B.), the Swedish Children’s Cancer Foundation (nos. TJ2019-0020 and PR-2019-0047 to N.G., PR2018-0095 to T.H.), the Swedish Society for Medical Research (to N.G.), Dr. Åke Olsson Foundation for Hematological Research (no. M19-0435, to N.G.), Felix Mindus Contribution to Leukemia Research (to N.G.), the Radiumhemmet Research Fund (no. 191282, to U.W.B.), the Crafoord Foundation (to P.S.), the Swedish Research Council (nos. 2015-00162, 2017-06095 to T.H., 2018-03406 to P.S.), the European Research Council (no. TAROX-695376 to T.H.), Swedish Cancer Society (no. CAN 2018/600 to T.H., 201287 PjF to P.S.), the Swedish Pain Relief Foundation (to T.H.), the Torsten and Ragnar Söderberg Foundation (to T.H.), the Helleday Foundation (to P.M., J.U., S.B. and C.B.J.P.), Vinnova (2018-00257, to T.H.), the Novo Nordisk Foundation (no. NNF19SA0059297, to T.H.) and the University of Sheffield and the Luxembourg National Research Fund under the FNR-ATTRACT program (no. A18/BM/11809970, to J.M.).