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
• Indication:
  In total 1 Indication(s)
  Renal cell carcinoma [ICD-11: 2C90]; Investigative; [1]
• 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]
• 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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]

• Molecule Alteration: Missense mutation; p.I103N (c.308T>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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]

• Molecule Alteration: Missense mutation; p.L115A (c.343_344delCTinsGC)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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]

• Molecule Alteration: Missense mutation; p.L115P (c.344T>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: 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]

• Molecule Alteration: Missense mutation; p.F53S (c.158T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [3]

• Molecule Alteration: Missense mutation; p.I103N (c.308T>A)
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting 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]

• Molecule Alteration: Missense mutation; p.L115P (c.344T>C)
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting 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)

Key Molecule: GTPase Hras (HRAS) [6]

• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: 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 blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]

• Molecule Alteration: Missense mutation; p.T798M (c.2393_2394delCAinsTG)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: 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]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [4]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MDA-H2774 cells; Ascites; Homo sapiens (Human); CVCL_0420
• Experiment for Molecule Alteration: Western blotting 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.