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]

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

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

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Missense mutation; p.L115P
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [2]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expression; Down-regulation
• 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: 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.