Drug Information

Drug (ID: DG01496) and It's Reported Resistant Information
Name
CI-1040
Synonyms
212631-79-3; CI-1040; PD184352; PD 184352; PD-184352; 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide; CI 1040; PD184352 (CI-1040); CI1040; 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; 2-((2-Chloro-4-iodophenyl)amino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide; 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide; PD-18435; UNII-R3K9Y00J04; C.I. 1040; CHEMBL105442; R3K9Y00J04; MFCD02683961; NCGC00189074-01; PD 184352CI-1040; CI-1040 (PD184352); DSSTox_CID_28871; DSSTox_RID_83140; DSSTox_GSID_48945; C17H14ClF2IN2O2; 2-[(2-CHLORO-4-IODOPHENYL)AMINO]-N-(CYCLOPROPYLMETHOXY)-3,4-DIFLUOROBENZAMIDE; CAS-212631-79-3; PD 184,352; MLS006010176; SCHEMBL570330; PD 184352, Free Base; GTPL5676; QCR-25; DTXSID8048945; CHEBI:91353; SYN1031; HMS3244G05; HMS3244G06; HMS3244H05; HMS3265I07; HMS3265I08; HMS3265J07; HMS3265J08; HMS3654I05; AOB87195; BCP01791; EX-A2202; ZINC1489691; Tox21_113363; BDBM50132260; NSC765695; s1020; AKOS022184333; Tox21_113363_1; CCG-269529; CS-0058; DB12429; NSC-765695; SB19417; NCGC00189074-03; NCGC00189074-05; AC-25483; AS-19373; HY-50295; SMR004701284; CI-1040,PD184352; DB-014962; CI-1040; PD184352; FT-0673543; SW219604-1; X7396; EC-000.2331; PD 184352(CI-1040); PD184352 - CI-1040; A25744; PD184352, >=98% (HPLC); 631C793; US8575391, 341; J-505572; BRD-K05104363-001-01-9; Q27076005; 2-(2-Chloro4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2-[(2-Chloro-4-iodophenyl)amino]-N-cyclopropylmethoxy)-3,4-difluorobenzamide; Benzamide, 2-((2-chloro-4-iodophenyl)amino)-N-(cyclopropylmethoxy)-3,4-difluoro-; CI-1040; ; ; 2-(2-Chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide
    Click to Show/Hide
Indication
In total 1 Indication(s)
Renal cell carcinoma [ICD-11: 2C90]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
Breast cancer [ICD-11: 2C60]
[2]
Melanoma [ICD-11: 2C30]
[3]
Target Serine/threonine-protein kinase mTOR (mTOR) MTOR_HUMAN [4]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
6
IsoSMILES
C1CC1CONC(=O)C2=C(C(=C(C=C2)F)F)NC3=C(C=C(C=C3)I)Cl
InChI
InChI=1S/C17H14ClF2IN2O2/c18-12-7-10(21)3-6-14(12)22-16-11(4-5-13(19)15(16)20)17(24)23-25-8-9-1-2-9/h3-7,9,22H,1-2,8H2,(H,23,24)
InChIKey
GFMMXOIFOQCCGU-UHFFFAOYSA-N
PubChem CID
6918454
ChEBI ID
CHEBI:91353
TTD Drug ID
D0ES1Q
DrugBank ID
DB12429
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
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.I103N (c.308T>A)
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae strain SY2002 4932
Experiment for
Molecule Alteration		 Kinase assay
Mechanism Description The missense mutation p.I103N (c.308T>A) in gene MAP2K1 cause the resistance of CI-1040 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.L115A (c.343_344delCTinsGC)
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae strain SY2002 4932
Experiment for
Molecule Alteration		 Kinase assay
Mechanism Description The missense mutation p.L115A (c.343_344delCTinsGC) in gene MAP2K1 cause the resistance of CI-1040 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.L115P (c.344T>C)
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae strain SY2002 4932
Experiment for
Molecule Alteration		 Kinase assay
Mechanism Description The missense mutation p.L115P (c.344T>C) in gene MAP2K1 cause the resistance of CI-1040 by unusual activation of pro-survival pathway
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) [5]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 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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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 BRAF kinase assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of CI-1040 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.F53S (c.158T>C)
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae strain SY2002 4932
Experiment for
Molecule Alteration		 Kinase assay
Mechanism Description The missense mutation p.F53S (c.158T>C) in gene MAP2K1 cause the sensitivity of CI-1040 by unusual activation of pro-survival pathway
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.I103N (c.308T>A)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
293T cells Breast Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description The missense mutation p.I103N (c.308T>A) in gene MAP2K1 cause the resistance of CI-1040 by aberration of the drug's therapeutic target
Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L115P (c.344T>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
293T cells Breast Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description The missense mutation p.L115P (c.344T>C) in gene MAP2K1 cause the resistance of CI-1040 by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Hras (HRAS) [6]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G12V (c.35G>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
A375 cells Skin Homo sapiens (Human) CVCL_0132
In Vivo Model Female athymic nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Caspase-Glo 3/7 luminogenic assay
Breast cancer [ICD-11: 2C60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Missense mutation
p.T798M (c.2393_2394delCAinsTG)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model BT474 cells Breast Homo sapiens (Human) CVCL_0179
MCF10A cells Breast Homo sapiens (Human) CVCL_0598
In Vivo Model Athymic female mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 HER2T798M sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.T798M (c.2393_2394delCAinsTG) in gene ERBB2 cause the resistance of CI-1040 by aberration of the drug's therapeutic target
Ovarian cancer [ICD-11: 2C73]
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) [4]
Sensitive Disease Ovarian cancer [ICD-11: 2C73.0]
 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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I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model SkOV3 cells Ovary Homo sapiens (Human) CVCL_0532
A2780 cells Ovary Homo sapiens (Human) CVCL_0134
OVCAR3 cells Ovary Homo sapiens (Human) CVCL_0465
MDA-H2774 cells Ascites Homo sapiens (Human) CVCL_0420
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 DAPI assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of CI-1040 by unusual activation of pro-survival pathway
References
Ref 1 Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352Mol Cell Biol. 2002 Nov;22(21):7593-602. doi: 10.1128/MCB.22.21.7593-7602.2002.
Ref 2 Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2Clin Cancer Res. 2013 Oct 1;19(19):5390-401. doi: 10.1158/1078-0432.CCR-13-1038. Epub 2013 Aug 15.
Ref 3 MEK1 mutations confer resistance to MEK and B-RAF inhibitionProc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6. doi: 10.1073/pnas.0905833106. Epub 2009 Nov 13.
Ref 4 KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancerBr J Cancer. 2008 Dec 16;99(12):2020-8. doi: 10.1038/sj.bjc.6604783. Epub 2008 Nov 18.
Ref 5 Gatekeeper mutations mediate resistance to BRAF-targeted therapiesSci Transl Med. 2010 Jun 9;2(35):35ra41. doi: 10.1126/scitranslmed.3000758.
Ref 6 Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway OncogenesCancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.

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