piperidines and ivosidenib

Conventional chemotherapy with cytarabine and anthracycline (often referred to as "7+3") has been used for many years in the treatment of acute myeloid leukemia (AML). Despite meaningful advances in areas of supportive care and transplantation, little progress has been made in developing new chemotherapy options. In 2018, The Food and Drug Administration (FDA) of the US approved several novel agents for AML treatment as follows: ivosidenib, an inhibitor of isocitrate dehydrogenase-1; venetoclax, a potent inhibitor of bcl2; and glasdegib, an inhibitor of hedgehog signaling pathway. Moreover, clinical trials of alvocidib (flavopiridol), an inhibitor of the CDK9, pevonedistat, an inhibitor of NEDD8, and APR-246, a reactivator of mutant p53, are in progress. These agents will either be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents to improve the outcome of AML therapy, and the results will guide the next stage of precision medicine in the treatment of AML.

Topics: Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cyclopentanes; Drug Approval; Flavonoids; Glycine; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Phenylurea Compounds; Piperidines; Pyridines; Pyrimidines; Sulfonamides; United States; United States Food and Drug Administration

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Topics: Acute Disease; Aminopyridines; Animals; Cell Line, Tumor; Doxycycline; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epigenesis, Genetic; Glycine; HL-60 Cells; Humans; Isocitrate Dehydrogenase; Isoenzymes; Leukemia, Myeloid; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mitochondria; Mutation; Oxadiazoles; Oxidative Phosphorylation; Piperidines; Pyridines; Triazines; Xenograft Model Antitumor Assays