Drug Information

Drug (ID: DG01641) and It's Reported Resistant Information

• Name: Enasidenib
• Synonyms: Enasidenib; 1446502-11-9; AG-221; AG-221 (Enasidenib); CC-90007 Free Base; IDHIFA; UNII-3T1SS4E7AG; AG 221; 2-Methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol; CC-90007; 3T1SS4E7AG; 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol; 2-Methyl-1-[(4-[6-(Trifluoromethyl)pyridin-2-Yl]-6-{[2-(Trifluoromethyl)pyridin-4-Yl]amino}-1,3,5-Triazin-2-Yl)amino]propan-2-Ol; 2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol; 2-Propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino]-1,3,5-triazin-2-yl]amino]-; 2-Propanol, 2-methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-; Enasidenib [INN]; enasidenibum; AG221; 2-methyl-1-({4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl}amino)propan-2-ol; AG-221(Enasidenib); AG-221; Enasidenib; Enasidenib; AG-221; Enasidenib (USAN/INN); Enasidenib [USAN:INN]; GTPL8960; CHEMBL3989908; SCHEMBL15102202; EX-A654; CHEBI:145374; HMS3873D03; AMY38698; BCP16041; BDBM50503251; MFCD29472245; NSC788120; s8205; AKOS026750439; ZINC222731806; CCG-269476; CS-5017; DB13874; NSC-788120; SB19193; NCGC00479249-03; NCGC00479249-05; AC-31318; AS-75164; HY-18690; FT-0700204; D10901; A857662; J-690181; Q27077182; B0084-470859; AG-221; AG 221; AG221; CC-90007; CC 90007; CC90007; 69Q
• Indication:
  In total 1 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 3; [1]
• Target: Serine/threonine-protein kinase B-raf (BRAF); BRAF_HUMAN; [1]
• Formula: 6
• IsoSMILES: CC(C)(CNC1=NC(=NC(=N1)C2=NC(=CC=C2)C(F)(F)F)NC3=CC(=NC=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)
• InChIKey: DYLUUSLLRIQKOE-UHFFFAOYSA-N
• PubChem CID: 89683805
• ChEBI ID: CHEBI:145374
• TTD Drug ID: D0M5XN
• VARIDT ID: DR0574
• DrugBank ID: DB13874

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [1]

• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [1]

• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R140G (c.418C>G)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R140W (c.418C>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R140L (c.419G>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R172G (c.514A>G)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R172W (c.514A>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R172M (c.515G>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R172S (c.516G>C)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [2]

• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Hematologic cancer [ICD-11: 2B3Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [3]

• Molecule Alteration: Missense mutation; p.R140K (c.418_419delCGinsAA)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [3]

• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Identified from the Human Clinical Data

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [1]

• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

References

• Ref 1: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsCancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13.
• Ref 2: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemiaBlood. 2017 Aug 10;130(6):722-731. doi: 10.1182/blood-2017-04-779405. Epub 2017 Jun 6.
• Ref 3: Abstract CT103: Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-0280.