SciLifeLab Drug Discovery Seminar & DDD Exit event: Thomas Helleday
December 8 @ 14:00 – 15:00 CET
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
Professor Thomas Helleday, Karolinska Institutet
SciLifeLab Drug Discovery Seminars, hosted by the DDD platform, is a series of educational lectures about recent developments, technologies, and trends in drug discovery and development that aims to enlighten, and spark a discussion, within the Swedish drug discovery community.
The folate metabolism enzyme MTHFD2 is consistently overexpressed in cancer but its roles are not fully characterized and current candidate inhibitors have limited potency for clinical development. Here we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and present optimised potent and selective nanomolar MTHFD2 inhibitors (MTHFD2i); protein co-crystal structures demonstrated binding to the active site of MTHFD2 and target engagement and that works in vitro and in vivo.
The results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. The work, done in collaboration with the SciLifeLab DDD platform, is accepted in the journal Nature Cancer and is the base for the creation of a new company: One-carbon therapeutics AB.