Therapeutics to Overcome the Differentiation Roadblock in Myelodysplastic Syndrome (MDS)

Novel Approaches and New Therapeutics

Michael Bollong (Scripps)

Rafael Bejar (UCSD)

Arnab Chatterjee (Scripps)

Myelodysplastic syndrome (MDS) is a pre-cancer condition involving mutations in the stem cells which give rise to the many cell types which compose blood. These mutations cause stem cells to produce red blood cells and other cell types less efficiently, conditions called cytopenias — complications to which most MDS patients succumb. Here, we have identified a class of anti-malarial medications, called Artemisinins, which overcome these mutations, making it such that stem cells can efficiently give rise to downstream blood types, thereby overcoming cytopenias. Artemisias have been used clinically to treat malaria — the discovery of which was awarded the Nobel prize in 2006 — but no Artemisinin drug is suitable for chronic oral dosing, which is required for treating MDS. With this grant, we will use medicinal chemistry to develop an Artemisinin derivative that can be orally dosed as therapy for this disease. We will also uncover how an off-target activity of this drug class results in this striking effect on mutated cells. Successful completion of this grant will deliver a preclinical candidate for the treatment of MDS, ready for IND-enabling safety studies, the next steps in advancing this candidate as a new drug.