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
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Phase 2; [1]
• 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]
• 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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 2 (MEK2) [1]

• Molecule Alteration: Missense mutation; p.V215E
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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
• In Vitro Model: 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]

• Molecule Alteration: Missense mutation; p.F129L
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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
• In Vitro Model: 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.

Breast cancer [ICD-11: 2C60]

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.L115P
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: 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.

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.