Enasidenib

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Enasidenib
Enasidenib.svg
Clinical data
Trade names Idhifa
Other namesAG-221
AHFS/Drugs.com Monograph
MedlinePlus a617040
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
Formula C19H17F6N7O
Molar mass 473.383 g·mol−1
3D model (JSmol)
  • CC(C)(CNC1=NC(=NC(=N1)NC2=CC(=NC=C2)C(F)(F)F)C3=NC(=CC=C3)C(F)(F)F)O
  • InChI=InChI=1S/C19H17F6N7O/c1-17(2,33)9-27-15-30-14(11-4-3-5-12(29-11)18(20,21)22)31-16(32-15)28-10-6-7-26-13(8-10)19(23,24)25/h3-8,33H,9H2,1-2H3,(H2,26,27,28,30,31,32)
  • Key:DYLUUSLLRIQKOE-UHFFFAOYSA-N

Enasidenib (INN; trade name Idhifa) is a medication used to treat relapsed or refractory acute myeloid leukemia in people with specific mutations of the isocitrate dehydrogenase 2 (IDH2) gene, determined by an FDA-approved IDH2 companion diagnostic test. [2] It is an inhibitor of IDH2. It was developed by Agios Pharmaceuticals and is licensed to Celgene for further development.

Contents

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [3]

Medical use

Enasidenib is used to treat relapsed or refractory acute myeloid leukemia in people with specific mutations of the IDH2 gene, determined by an FDA-approved IDH2 companion diagnostic test. [2]

Adverse effects

The main serious adverse effect of enasidenib is differentiation syndrome. [4]

Pharmacology

Isocitrate dehydrogenase is a critical enzyme in the citric acid cycle. Mutated forms of IDH produce high levels of the (R)-enantiomer of 2-hydroxyglutarate (R-2-HG) and can contribute to the growth of tumors. IDH1 catalyzes this reaction in the cytoplasm, while IDH2 catalyzes this reaction in mitochondria. Mutations of IDH2 are more common than IDH1 mutations, 8 to 19% compared to 7 to 14% respectively, [2] in those affected with AML. Enasidenib disrupts this cycle by decreasing total (R)-2-HG levels in the mitochondria.[ medical citation needed ]

History

The U.S. Food and Drug Administration (FDA) granted the application for enasidenib fast track designation and orphan drug designation for acute myeloid leukemia in 2014. [4]

Enasidenib was approved by the FDA in August 2017, for relapsed or refractory acute myeloid leukemia (AML) in people with specific mutations of the IDH2 gene, determined by an FDA-approved IDH2 companion diagnostic test. [2] [5] [6]

Related Research Articles

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<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

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<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.

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Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.

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Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.

<span class="mw-page-title-main">IDH2</span>

Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.

<span class="mw-page-title-main">IDH3G</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">IDH1</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

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Agios Pharmaceuticals Inc. is a public American pharmaceutical company pioneering therapies for genetically defined diseases, with a near-term focus on developing therapies for hemolytic anemias. The company was founded in 2008 by Lewis Cantley, Tak Mak and Craig Thompson. Agios is a Delaware corporation headquartered in Cambridge, Massachusetts. The company tendered an initial public offering in July 2013.

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Olutasidenib, sold under the brand name Rezlidhia, is an anticancer medication used to treat relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor. It is taken by mouth.

References

  1. ↑ "Summary Basis of Decision (SBD) for Idhifa". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  2. 1 2 3 4 Kim ES (October 2017). "Enasidenib: First Global Approval". Drugs. 77 (15): 1705–1711. doi:10.1007/s40265-017-0813-2. PMID   28879540. S2CID   7685848.
  3. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  4. 1 2 Brunton LL, Hilal-Dandan R, Knollmann BC (5 December 2017). Goodman & Gilman's the pharmacological basis of therapeutics (13th ed.). New York: McGraw Hill Education. ISBN   9781259584732. OCLC   993810322.
  5. ↑ "FDA Approves New Treatment for Leukemia". Genetic Engineering & Biotechnology News (GEN). August 2, 2017.
  6. ↑ "Press release: FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML". FDA. August 1, 2017.
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