One-carbon therapeutics AB is tackling the most difficult to treat cancers, inflammation and autoimmune diseases by targeting the disease specific one-carbon metabolism pathway, representing a novel way of attacking the DNA damage response (DDR). Here is the place where create innovative precision oncology medicines are born.
Co-founded in 2020 by the Helleday Laboratory, with over 20 years of experience in DNA damage response (DDR) biology, we are taking the previous success of discovering the synthetic lethal concept for the treatment of BRCA mutated cancer with PARP inhibitors to a new level; attacking difficult to treat cancers using synthetic lethality in the one-carbon pathway to target the DNA damage response for treatment of cancer and inflammation.
At One-carbon therapeutics we apply cutting-edge science to create first-in-class treatments against MTHFD1/2 cancer proteins and related targets. Our development is guided by advanced biomarkers identified using primary cancer patient’s tumors.
Unique strategy
MTHFD1/2
Our primary targets are MTHFD1/2 isoenzyme proteins that regulate one-carbon metabolism, often upregulated in multiple cancers. MTHFD2 is an oncofoetal protein expressed during embryogenesis, silenced in normal adult cells, and then re-expressed in cancer. Both proteins have been validated as anti-cancer targets by numerous independent laboratories. We are proud to have made a first-in-class, low nanomolar potent inhibitor of MTHFD1/2 for clinical development using state-of-the-art structural and medicinal chemistry approaches.
DNA replication
A key hallmark of all DDR inhibitors is that they cause DNA replication stress that kill cells, but the challenge is doing this selectively only in cancer cells. Using the DNA fiber assay (DNA combing), we can visualize replicating DNA molecules and show a cancer-specific reduction of replication fork speed and induction of replication stress after using MTHFD1/2 inhibitors (MTHFD1/2i). In normal cells, we do not see such effects emphasizing the specificity of our approach.
DDR and Cellular Metabolism
Cancer cells alter their metabolic pathways to meet the increased demand for energy and building blocks needed for rapid cell proliferation and survival. Yet, these alterations come with a cost of increased DNA damage that, if left unrepaired, will lead to cancer cell death. For this reason, cancer cells rely heavily on DNA damage response (DDR) pathways to maintain genome integrity. Targeting these pathways is a common approach to treating cancer. More recently, compelling findings indicate a connection between cancer metabolism and DNA damage repair processes. Metabolic enzymes represent a crucial group of factors within the DDR, opening novel ways to target these cancer vulnerabilities therapeutically.
Many years of experience in oncology drug discovery and development, identified and brought first-in-class DDR targets to clinical trials. The co-founder of One-carbon therapeutics pioneered the PARP-BRCA synthetic lethal concept.
Building on frontline research and developing first-in-class treatments for a new emerging area within the DDR space. Advanced structure-guided medicinal chemistry and unique mechanism of action.
Targeting cancers with high unmet clinical need using state-of-the-art ex vivo screening and defined biomarker-driven patient selection. Employing emerging ex vivo screening methods for increased accuracy.
Professor Johann de Bono, Head of the Division of Clinical Studies and Drug Development Unit and Experimental Cancer Medicine at The Institute of Cancer Research
We look forward to meeting you there!
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