Drug Information

Drug (ID: DG00205) and It's Reported Resistant Information
Name
PD-0325901
Synonyms
PD 0325901; PD 325901; PD0325901; PD325901; PD-325901; S06-0029; N-[((R)-2,3-dihydroxypropyl)oxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide; N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodo-phenyl)amino]benzamide; N-{[(2R)-2,3-dihydroxypropyl]oxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
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Indication
In total 1 Indication(s)
Breast cancer [ICD-11: 2C60]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Breast cancer [ICD-11: 2C60]
[1]
Colorectal cancer [ICD-11: 2B91]
[1]
Target MAPK/ERK kinase kinase (MAP3K) NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C16H14F3IN2O4
IsoSMILES
C1=CC(=C(C=C1I)F)NC2=C(C=CC(=C2F)F)C(=O)NOC[C@@H](CO)O
InChI
1S/C16H14F3IN2O4/c17-11-3-2-10(16(25)22-26-7-9(24)6-23)15(14(11)19)21-13-4-1-8(20)5-12(13)18/h1-5,9,21,23-24H,6-7H2,(H,22,25)/t9-/m1/s1
InChIKey
SUDAHWBOROXANE-SECBINFHSA-N
PubChem CID
9826528
ChEBI ID
CHEBI:88249
TTD Drug ID
D0K0YC
DrugBank ID
DB07101
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  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
Colorectal cancer [ICD-11: 2B91]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: MAPK/ERK kinase 2 (MEK2) [1]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.V215E
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEk signaling pathway Activation hsa04010
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
HCT-116 MEk-R cells Colon Homo sapiens (Human) CVCL_V401
Experiment for
Molecule Alteration		 Exome sequencing assay
Experiment for
Drug Resistance		 BrdUrd assay
Mechanism Description The RAS/RAF/MEk pathway is activated in more than 30% of human cancers, most commonly via mutation in the k-ras oncogene and also via mutations in BRAF. Importantly, in all cases the MEk-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPk) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERk1/2 kinases. These data suggest that tumors with acquired MEk inhibitor resistance remain dependent on the MAPk pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEk target.
Key Molecule: MAPK/ERK kinase 1 (MEK1) [1]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Molecule Alteration Missense mutation
p.F129L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEk signaling pathway Activation hsa04010
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
HCT-116 MEk-R cells Colon Homo sapiens (Human) CVCL_V401
Experiment for
Molecule Alteration		 Exome sequencing assay
Experiment for
Drug Resistance		 BrdUrd assay
Mechanism Description The RAS/RAF/MEk pathway is activated in more than 30% of human cancers, most commonly via mutation in the k-ras oncogene and also via mutations in BRAF. Importantly, in all cases the MEk-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPk) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERk1/2 kinases. These data suggest that tumors with acquired MEk inhibitor resistance remain dependent on the MAPk pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEk target.
Pancreatic cancer [ICD-11: 2C10]
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Drug Sensitive Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-139 [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-200b [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK-EGFR-PI3K signalling pathway Regulation N.A.
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-141 [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK-EGFR-PI3K signalling pathway Regulation N.A.
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-200c [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK-EGFR-PI3K signalling pathway Regulation N.A.
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-155 [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-200a [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK-EGFR-PI3K signalling pathway Regulation N.A.
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-135b [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Key Molecule: hsa-miR-429 [2]
Sensitive Disease Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MEK-EGFR-PI3K signalling pathway Regulation N.A.
In Vitro Model Panc1 cells Pancreas Homo sapiens (Human) CVCL_0480
CFPAC1 cells Pancreas Homo sapiens (Human) CVCL_1119
HPAF-II cells Pancreatic Homo sapiens (Human) CVCL_0313
Capan-2 cells Pancreas Homo sapiens (Human) CVCL_0026
BxPC-3 cells Pancreas Homo sapiens (Human) CVCL_0186
In Vivo Model Female 7- to 9-week-old Nu/Nu mice (Harlan, FoxN1/nude) Mus musculus
Experiment for
Molecule Alteration		 Western blot
Experiment for
Drug Resistance		 Cell growth inhibition assays; Apoptosis analysis
Mechanism Description Since miR200 family is known to be crucially involved in regulating epithelial-to-mesenchymal transition (EMT), our findings support the notion that molecular programs regulating differentiation status of PDA cells determine susceptibility to combinations of MEK and EGFR inhibitors.
Breast cancer [ICD-11: 2C60]
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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 Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.L115P
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation RAS/RAF/MEk signaling pathway Activation hsa04010
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
HCT-116 MEk-R cells Colon Homo sapiens (Human) CVCL_V401
Experiment for
Molecule Alteration		 Exome sequencing assay
Experiment for
Drug Resistance		 BrdUrd assay
Mechanism Description The RAS/RAF/MEk pathway is activated in more than 30% of human cancers, most commonly via mutation in the k-ras oncogene and also via mutations in BRAF. Importantly, in all cases the MEk-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPk) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERk1/2 kinases. These data suggest that tumors with acquired MEk inhibitor resistance remain dependent on the MAPk pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEk target.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [3]
Sensitive Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF7 cells Breast Homo sapiens (Human) CVCL_0031
Experiment for
Molecule Alteration		 Immunoblotting assay
Experiment for
Drug Resistance		 Cell cycle assay; Tissue microarrays staining assay
Mechanism Description MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance.
References
Ref 1 ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther. 2012 May;11(5):1143-54. doi: 10.1158/1535-7163.MCT-11-1010. Epub 2012 Mar 8.
Ref 2 The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomasMol Cancer Ther. 2013 Oct;12(10):1994-2005. doi: 10.1158/1535-7163.MCT-13-0206. Epub 2013 Jul 19.
Ref 3 A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERalpha-positive luminal breast cancer. Biochem Pharmacol. 2022 Oct;204:115233.

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