In the late 2016, the connection between Acute Myelogenous Leukemia (AML) and dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from Pharma as possible new therapeutic target for AML. Since the COVID-19 outbreak, the use of hDHODH inhibitors as Host Targeting Antivirals (HTA) became one of the most promising therapeutic options for COVID-19 treatment. By using an innovative 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), superior to the lead brequinar (EC50 = 249 nM (THP1) and 189 nM (U937)), currently in phase I/II clinical trial for AML. By leading the cell into pyrimidine starvation, MEDS433 inhibits the in vitro replication of a large panel of viruses. On SARS-CoV-2, the replication is inhibited in the low nM range (EC50 = 63 nM), being MEDS433 five folds superior of the Merck antiviral Molnupiravir (EC50 = 300 nM), recently approved for COVID-19. In this occasion, beside detailing the MEDS433 design, unpublished pharmacokinetics, metabolism, toxicity (acute/subacute) as well as in vivo efficacy in different models (leukemic xenograft and IV (mouse, IP, PO) and influenza) are presented; studies that open the incoming certified preclinical studies necessary for the Phase I clinical trial for the aforementioned pathologies. The strategy (theoretical design, modeling, synthesis, SAR, X-ray crystallography, in vitro biological assays (enzymatic activity and cell based), in vitro ADME) that allowed the discovery of MEDS433 backup compounds, superior in terms of in vitro efficacy and with a reduced toxicity profile, are also presented.

Potent human dihydroorotate dehydrogenase inhibitors based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold against acute myelogenous leukemia and COVID-19: Steps close to clinic

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.