Compositions and methods for inhibiting dihydroorotate dehydrogenase
AssigneeClear Creek Bio, Inc.
InventorsVikram S. Kumar, David P. Hesson
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Abstract
The invention provides therapeutic compositions that contain an inhibitor of dihydroorotate dehydrogenase (DHODH) and promote sustained elevation of dihydroorotate (DHO) levels in a patient. The compositions are useful for treating disorders associated with unregulated DHODH activity, such as acute myeloid leukemia. The invention also provides methods of determining therapeutically effective doses of compositions that contain a DHODH inhibitor. The invention further provides methods of synthesis of 2-(2′-halo-1-1′-biphenyl-4-yl)-quinoline carboxylic acids, which are useful as DHODH inhibitors.
Claims68
A composition comprising an inhibitor of dihydroorotate dehydrogenase in a therapeutically effective amount that raises or maintains a level of dihydroorotate above a threshold level in a subject for a period of more than 72 hours.
A composition comprising an inhibitor of dihydroorotate dehydrogenase in a therapeutically effective amount that results in a level of dihydroorotate being at least about 25 ng/mL in a subject.
An oral formulation comprising an inhibitor of dihydroorotate dehydrogenase in a therapeutically effective amount that raises or maintains a level of dihydroorotate above a threshold level in a subject for a period of more than 72 hours.
A method of determining a therapeutically effective dose of a dihydroorotate dehydrogenase (DHODH) inhibitor to be provided to a subject to treat a disorder, the method comprising:
- determining a therapeutically effective dose of a DHODH inhibitor based on a measured level of dihydroorotate (DHO) in a sample from a subject, wherein the therapeutically effective dose of the DHODH inhibitor inhibits DHODH to an extent that at least one sign or symptom of the disorder is reduced or eliminated.
A method of adjusting a dosing regimen of a dihydroorotate dehydrogenase (DHODH) inhibitor to treat a disorder in a subject that is currently on the dosing regimen, the method comprising:
- receiving information regarding a measured level of dihydroorotate (DHO) in a sample from a subject having a disorder;
- comparing the received information to a reference that provides an association of a measured level of DHO with a recommended dosage adjustment of a DHODH inhibitor;
- and
- adjusting, based on the comparing step, the dosing regimen of the DHODH inhibitor so that a next dose of the DHODH inhibitor in the dosing regimen results in a level of DHO being raised or maintained above a threshold level, the threshold level being indicative that an amount of the DHODH inhibitor in the subject is sufficient to reduce or eliminate at least one sign or symptom of the disorder.
Dependencies are inferred from the claim text.