Targeting Acute Myelogenous Leukemia using potent human dihydroorotate dehydrogenase inhibitors based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold: from academy to clinic

The connection in the late 2016 beetwen Acute Myelogenous Leukemia (AML) and dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharmaceutical companies who have recognized a possible new therapeutic target for AML. In 2018, using a bioisosteric approach supported by structure-based techniques, we discovered MEDS433, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1 and U937) in the low nM range (EC50 = 40 and 26 nM), which shows better qualities than brequinar (EC50 = 249 nM on THP1 and 189 nM on U937), currently in phase I/II clinical trial for AML. These incredible in vitro results encouraged us to deeper the MEDS433 properties in order to optimize the design of the future certified preclinical study necessary to open the doors of the Phase I clinical trial. In this occasion, the pharmacokinetics, metabolism, toxicity as well as the in vivo efficacy in leukemic xenograft mouse model (IP, PO) of MEDS433 are presented. The strategy that allowed the discovery of MEDS700, a MEDS433 backup compound, superior to MEDS433 itself in terms of in vitro efficacy and minor toxicity is also presented.