Organic Chemistry: Current Research
Open Access

A new possibility on Acute Myelogenous Leukemia (AML): Targeting myeloid differentiation using potent and innovative human Dihydroorotate Dehydrogenase (hDHODH) inhibitors

10^th European Organic Chemistry Congress

March 21-22, 2019 | Rome, Italy

Marco L. Lolli, Stefano Sainas, Agnese C. Pippione, Elisa Lupino, Marta Giorgis, Paola Circosta, Valentina Gaidano, Davide Bonanni, Alessandro Cignetti, Salam Al-Karadaghi, Donatella Boschi and Giuseppe Saglio

University of Torino, Italy

Posters & Accepted Abstracts: Organic Chem Curr Res

Abstract :

Acute myelogenous leukemia (AML) is a clinically most devastating disease with dismal prognosis and survival rate. Efforts to identify new therapeutic targets to overcome myeloid differentiation blockade were largely unsuccessful until the breakthrough study in 2016 by Sykes et al. (Cell 2016, 167, 171) who demonstrated that inhibition of human dihydroorotate dehydrogenase (hDHODH) enables myeloid differentiation in both human and mouse AML models. Since then the development of potent and optimized hDHODH inhibitors has become a potential new strategy for the treatment of AML. Starting from innovative bioisosteric hypothesis and using stateof- the-art designing paradigms, including crystallographic and molecular modelling studies, biological assays (cell viability, proliferation, cytotoxicity, immunosuppression and myeloid differentiation), we have recently discovered a novel small molecule (cpd 1), representative of a novel class of hDHODH inhibitors based on a hydroxylpyrazolepyridine scaffold, that is able to restore the myeloid differentiation in leukemia cell lines at a 1-log lower concentration compared to the lead brequinar, causing a massive death of leukemic cells. To our knowledge, cpd 1 is one of the most potent and safe hDHODH inhibitor so far discovered. for their trauma needs and many without any referral to address these outstanding issues.