Drug Information

Drug (ID: DG01506) and It's Reported Resistant Information
Name
E6201
Synonyms
E6201; UNII-CZP9GB25HO; E-6201; CZP9GB25HO; E 6201; 603987-35-5; ER-806201; (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-benzo[c][1]oxacyclotetradecine-1,7(8H)-dione; (4~{S},5~{R},6~{Z},9~{S},10~{S},12~{E})-16-(ethylamino)-4,5-dimethyl-9,10,18-tris(oxidanyl)-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione; GTPL7836; SCHEMBL6983345; CHEMBL1097999; BDBM50515043; ZINC34374629; DB11687; (3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione; HY-15496; CS-0006796; J-504641; Q27077143; (4S,5R,6Z,9S,10S,12E)-16-(ethylamino)-9,10,18-trihydroxy-4,5-dimethyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione; (4S,5R,6Z,9S,10S,12E)-16-ethylamino-9,10,18-trihydroxy-4,5-dimethyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione; 1H-2-Benzoxacyclotetradecin-1,7(8H)-dione, 14-(ethylamino)-3,4,9,10-tetrahydro-8,9,16-trihydroxy-3,4-dimethyl-, (3S,4R,5Z,8S,9S,11E)-; 1H-2-Benzoxacyclotetradecin-1,7(8H)-dione, 14-(ethylamino)-3,4,9,10-tetrahydro-8,9,16-trihydroxy-3,4-dimethyl-, (3S,4R,5Z,8S,9S,11E) -
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Indication
In total 4 Indication(s)
Melanoma [ICD-11: 2C30]
Phase 2
[1]
Non-small-cell lung cancer [ICD-11: 2C25]
Phase 2
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Phase 2
[1]
Thyroid cancer [ICD-11: 2D10]
Phase 2
[1]
Structure
Target ERK activator kinase 1 (MEK1) MP2K1_HUMAN [2]
ERK activator kinase 2 (MEK2) MP2K2_HUMAN [2]
MAPK/ERK kinase kinase (MAP3K) NOUNIPROTAC [2]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
2
IsoSMILES
CCNC1=CC\\2=C(C(=C1)O)C(=O)O[C@H]([C@@H](/C=C\\C(=O)[C@H]([C@H](C/C=C2)O)O)C)C
InChI
InChI=1S/C21H27NO6/c1-4-22-15-10-14-6-5-7-16(23)20(26)17(24)9-8-12(2)13(3)28-21(27)19(14)18(25)11-15/h5-6,8-13,16,20,22-23,25-26H,4,7H2,1-3H3/b6-5+,9-8-/t12-,13+,16+,20+/m1/s1
InChIKey
MWUFVYLAWAXDHQ-HMNLTAHHSA-N
PubChem CID
10172827
TTD Drug ID
D0T5DP
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D835Y (c.2503G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK/ERK signaling pathway Inhibition hsa04011
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model NOG mouse Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Trypan blue dye exclusion method assay; FACS assay
Mechanism Description E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D835G (c.2504A>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK/ERK signaling pathway Inhibition hsa04011
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model NOG mouse Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Trypan blue dye exclusion method assay; FACS assay
Mechanism Description E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.
Acute lymphocytic leukemia [ICD-11: 2B33]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D835G (c.2504A>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK/ERK signaling pathway Inhibition hsa04011
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model NOG mouse Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Trypan blue dye exclusion method assay; FACS assay
Mechanism Description E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D835Y (c.2503G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK/ERK signaling pathway Inhibition hsa04011
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model NOG mouse Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Trypan blue dye exclusion method assay; FACS assay
Mechanism Description E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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420
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580
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
G-361 cells Skin Homo sapiens (Human) CVCL_1220
MDA-MB-435s cells Breast Homo sapiens (Human) CVCL_0622
SEKI cells Skin Homo sapiens (Human) CVCL_3162
HMV-1 cells Uterus Homo sapiens (Human) CVCL_8233
HMCB cells Skin Homo sapiens (Human) CVCL_3317
CHL-1 cells Pleural effusion Homo sapiens (Human) CVCL_1122
Experiment for
Molecule Alteration		 Western blot analysis; Immunohistochemistry assay
Experiment for
Drug Resistance		 WST-8 assay
References
Ref 1 The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 MutationsCancer Res. 2016 Mar 15;76(6):1528-37. doi: 10.1158/0008-5472.CAN-15-1580. Epub 2016 Jan 28.
Ref 2 Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical modelMol Cancer Ther. 2014 Apr;13(4):823-32. doi: 10.1158/1535-7163.MCT-13-0667. Epub 2014 Jan 21.

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