Therapeutics to overcome the differentiation roadblock in Myelodysplastic Syndrome (MDS)

In healthy individuals, stem cells in the bone marrow, called hematopoietic stem cells, give rise to all cells of the blood through a process called hematopoiesis. Due to aging and mutations, this process can go awry, leading to inefficient hematopoiesis with certain cellular populations being depleted relative to others, a condition called myelodysplastic syndrome, or MDS. The goal of this award was to develop a small molecule therapeutic that could overcome this roadblock in hematopoiesis in MDS patients. We found that an existing class of semi-synthetic medications for treating malaria called Artemisinins could effectively differentiate MDS cells, overcoming this roadblock. Here, we used an expansive medicinal chemistry campaign to optimize the drug likeness of certain Artemisinins for the safety and efficacy required as a once-a-day oral medication. We showed that this class of compounds shows a broad effect in both early and more advanced stages of disease, and we delineated a novel mechanism that is distinct from how Artemisinins act to kill the malaria parasite. Ultimately, we have delivered a therapeutic candidate that can be further progressed through later stage toxicity work, en route to providing a safe and generalizable therapeutic for broadly treating MDS