2 research outputs found
Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors
Human dihydroorotate dehydrogenase
(<i>h</i>DHODH) catalyzes
the rate-limiting step in de novo pyrimidine biosynthesis, the conversion
of dihydroorotate to orotate. <i>h</i>DHODH 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 <i>h</i>DHODH inhibitors,
which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5-<i>a</i>]pyridine, that has been designed starting from brequinar,
one of the most potent <i>h</i>DHODH inhibitors. A combination
of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency
in vitro and is superior in terms of cytotoxicity and immunosuppression.
Compound <b>4</b> 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 <i>h</i>DHODH inhibitors
Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors
Human dihydroorotate dehydrogenase
(<i>h</i>DHODH) catalyzes
the rate-limiting step in de novo pyrimidine biosynthesis, the conversion
of dihydroorotate to orotate. <i>h</i>DHODH 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 <i>h</i>DHODH inhibitors,
which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5-<i>a</i>]pyridine, that has been designed starting from brequinar,
one of the most potent <i>h</i>DHODH inhibitors. A combination
of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency
in vitro and is superior in terms of cytotoxicity and immunosuppression.
Compound <b>4</b> 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 <i>h</i>DHODH inhibitors