Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

Abstract

Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.

The Synergism Between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia

“…The inhibition of Dihydroorotate Dehydrogenase (DHODH) has recently been found to induce differentiation in several models of Acute Myeloid Leukemia (AML), both in vitro and in vivo [1]. From this seminal discovery, several academic and industrial research groups, including ours, have designed new and more potent DHODH inhibitors, confirming original results and extending the knowledge about this topic [2,3,4,5]. Transcriptome analyses revealed that leukemic cells treated with DHODH inhibitors upregulate genes related to apoptosis and differentiation, and downregulate protein translation-related genes, impairing protein synthesis [4,5].…”

“…MEDS433 is a new, potent DHODH inhibitor, developed and characterized by our group, which can induce differentiation in multiple AML cell lines, at a 1-log lower concentration compared to brequinar [2]. Here we show that MEDS433 also has a strong apoptotic effect on several AML cell lines, again at a 1-log lower concentration compared to brequinar (Fig.…”

A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode

“…Recently, a series of hDHODH inhibitors were discovered by scaffold-hopping strategy or structural modification based on previous reported lead compounds [16,17] In our instance, the active compounds were selected based on in vitro screening. Our screening discovered a novel class of human DHODH inhibitors, which have a 6-isopropyl-1,5,6,7-tetrahydro-4Hbenzo[d] [1,2,3]triazol-4-one scaffold.…”

“…Chemical structures and in vitro inhibitory activities of human DHODH inhibitors. of teriflunomide is from the reference[17].…”

Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition

“…Some pyrimidine biosynthesis inhibitors also exhibit broad-spectrum antiviral activity in vitro [1][2][3][17][18][19] and in vivo [20][21][22], opening new fields of application for this class of antimetabolites. In this context, the identification of novel DHODH inhibitors with original chemical and pharmacological properties has become a priority to overcome the limitations of existing molecules [23][24][25][26][27].…”