Abstract
Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Dihydroorotate Dehydrogenase*
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Drug Discovery
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacokinetics
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Enzyme Inhibitors* / pharmacology
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Enzyme Inhibitors* / therapeutic use
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Humans
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Leukemia, Myeloid, Acute* / drug therapy
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Molecular Docking Simulation
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Oxidoreductases Acting on CH-CH Group Donors* / antagonists & inhibitors
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Oxidoreductases Acting on CH-CH Group Donors* / metabolism
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Quinolones / chemical synthesis
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Quinolones / chemistry
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Quinolones / pharmacokinetics
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Quinolones / pharmacology
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Quinolones / therapeutic use
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Rats
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Structure-Activity Relationship
Substances
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Dihydroorotate Dehydrogenase
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Oxidoreductases Acting on CH-CH Group Donors
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Enzyme Inhibitors
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Antineoplastic Agents
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Quinolones