Abstract: The invention provides combination therapies for the treatment of cancer. The combination therapies include a first agent that alters a metabolic pathway and a second agent that targets the metabolic pathway. The combination therapies are useful for treating cancers having tumor cells with different phenotypes, such as cancers of the blood, breast, colon, and prostate.

Abstract: The invention provides therapeutic methods that include providing to a subject an inhibitor of dihydroorotate dehydrogenase (DHODH) and a second therapeutic agent. The methods are useful for treating cancers, such as leukemias.

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.

Abstract: The invention provides compositions and methods for treating conditions in a subject by providing an inhibitor of inosine phosphate dehydrogenase that promotes decreased levels of guanosine triphosphate and/or increased levels of hypoxanthine.

Abstract: The invention provides compositions and methods for treating conditions in a subject by inhibiting inosine monophosphate dehydrogenase. The invention provides compositions and methods that provide periods of sustained inhibition of inosine monophosphate dehydrogenase followed by periods in which enzyme activity is not inhibited. The invention also provides methods that include monitoring inhibition of inosine monophosphate dehydrogenase via analysis of GTP levels.

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.

Abstract: The invention provided methods of treating viral infections, such as COVID-19, by providing an agent that inhibits a nucleotide synthesis pathway. In certain methods, the agent is an inhibitor of dihydroorotate dehydrogenase, such as a brequinar. In certain methods, brequinar is provided to a subject according to a dosing regimen that tailors levels of the drug in the lungs to achieve optimal therapeutic benefit. The dosing regimen may include defined levels of brequinar administered to the subject or defined levels of brequinar attained the lungs of the subject. The invention also provides combination therapies in which an inhibitor of dihydroorotate dehydrogenase is provided together with a second therapeutic agent.

Abstract: The invention provided methods of treating viral infections, such as COVID-19, by providing an agent that inhibits a nucleotide synthesis pathway. In certain methods, the agent is an inhibitor of dihydroorotate dehydrogenase, such as a brequinar. In certain methods, brequinar is provided to a subject according to a dosing regimen that tailors levels of the drug in the lungs to achieve optimal therapeutic benefit. The dosing regimen may include defined levels of brequinar administered to the subject or defined levels of brequinar attained the lungs of the subject. The invention also provides combination therapies in which an inhibitor of dihydroorotate dehydrogenase is provided together with a second therapeutic agent.

Abstract: The invention provides compositions containing a stable crystalline form of brequinar and methods of making such composition. The invention also provides methods of using such compositions to treat a condition in a subject.

Abstract: The invention provided methods of treating viral infections, such as COVID-19, by providing an agent that inhibits a nucleotide synthesis pathway. In certain methods, the agent is an inhibitor of dihydroorotate dehydrogenase, such as a brequinar. In certain methods, brequinar is provided to a subject according to a dosing regimen that tailors levels of the drug in the lungs to achieve optimal therapeutic benefit. The dosing regimen may include defined levels of brequinar administered to the subject or defined levels of brequinar attained the lungs of the subject. The invention also provides combination therapies in which an inhibitor of dihydroorotate dehydrogenase is provided together with a second therapeutic agent.

Abstract: The invention provides compositions containing a stable crystalline form of brequinar and methods of making such composition. The invention also provides methods of using such compositions to treat a condition in a subject.

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.

Abstract: The invention provides methods for adjusting a drug dosing regimen, including a drug dosage and schedule of administration, in individuals who have previously received at least one dose of the drug. Adjustments to the dosage and/or schedule are made based on measured levels of the drug or metabolite of the drug and a biomarker of engagement of the drug with its target. The methods are useful for administration of therapeutic agents, such as brequinar, that alter metabolic pathways.

Abstract: The invention provides methods for adjusting a drug dosing regimen, including a drug dosage and schedule of administration, in individuals who have previously received at least one dose of the drug. Adjustments to the dosage and/or schedule are made based on measured levels of the drug or metabolite of the drug and a biomarker of engagement of the drug with its target. The methods are useful for administration of therapeutic agents, such as brequinar, that alter metabolic pathways.

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.

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.

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.

Abstract: The invention provides methods of determining a therapeutically effective dose of an agent that targets a metabolic pathway based on measured levels of a metabolite in the pathway. The methods, which may include providing the agent in a therapeutically effective dose, are useful for treating disorders, such as cancer, in a subject. The invention also provides methods for assessing the impact of a therapeutic agent on a tumor in a subject by monitoring, in real time, metabolism of a molecule in the tumor, oxygenation of the tumor, or both. The invention further provides devices that determine a therapeutically effective dose of an agent that targets a metabolic pathway based on measured levels of a metabolite in the pathway and notify a subject to administer the dose.

Abstract: The invention provides methods of treating brain cancer by providing an agent that inhibits an enzyme in a metabolic pathway in a cancer cell. In some methods of the invention, the agent is an inhibitor of dihydroorotate dehydrogenase. The invention also provides methods of determining a dosage of the therapeutic agent based on measured levels of a metabolite in the pathway.

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.