Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-<i>a</i>]pyridine Scaffold: SAR of the Biphenyl Moiety

Abstract

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (<i>h</i>DHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound <b>1</b>, a potent <i>h</i>DHODH inhibitor (IC₅₀ = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC₅₀ = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC₅₀ = 265 nM). Herein, we investigate the <b>1</b> drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, <b>17</b> is characterized by higher potency in inducing myeloid differentiation (EC₅₀ = 17.3 nM), strong proapoptotic properties (EC₅₀ = 20.2 nM), and low cytotoxicity toward non-AML cells (EC₃₀(Jurkat) > 100 μM).