Drug Information

Drug (ID: DG01538) and It's Reported Resistant Information

• Name: PLX4720
• Synonyms: PLX-4720; 918505-84-7; PLX4720; N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; PLX 4720; N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide; UNII-EQY31RO8HA; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide; EQY31RO8HA; CHEBI:90295; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-1-sulfonamide; N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide; C17H14ClF2N3O3S; N-[3-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide; a,a-dimethoxytoluene; 3c4c; MLS006010065; SCHEMBL133733; GTPL5703; CHEMBL1230020; BDBM25617; AMY2871; DTXSID10238711; EX-A186; SYN1069; HMS3244C03; HMS3244C04; HMS3244D03; HMS3265I09; HMS3265I10; HMS3265J09; HMS3265J10; HMS3654M10; HMS3750K11; HMS3884C05; ACT06829; AOB87700; BCP01754; PLX-4720,PLX4720; BBL102256; MFCD14635203; NSC757438; s1152; STL556055; ZINC39059267; AKOS015919071; CCG-268810; CS-0094; DB06999; NSC-757438; NCGC00187911-01; NCGC00187911-02; NCGC00187911-06; 1-Propanesulfonamide, N-[3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-; AC-23171; AS-19376; HY-51424; SMR004701225; DB-003736; FT-0673969; SW218119-2; X7406; A19411; Raf Kinase Inhibitor V - CAS 918505-84-7; 505P847; J-522979; BRD-K16478699-001-01-9; Q27088418; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]pr opane-1-sulfonamide; propane-1-sulfonic acid [3-(5-chloro-1h-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Propane-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-amide
• Indication:
  In total 4 Indication(s)
  Ovarian cancer [ICD-11: 2C73]; Phase 1; [1]
  Ovarian cancer [ICD-11: 2C73]; Phase 1; [1]
  Pancreatic cancer [ICD-11: 2C10]; Phase 1; [1]
  Prostate cancer [ICD-11: 2C82]; Phase 1; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Melanoma [ICD-11: 2C30]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Melanoma [ICD-11: 2C30]; [4]
• Target: Poly [ADP-ribose] polymerase (PARP); NOUNIPROTAC; [5]
• Formula: 6
• IsoSMILES: CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)Cl)F
• InChI: InChI=1S/C17H14ClF2N3O3S/c1-2-5-27(25,26)23-13-4-3-12(19)14(15(13)20)16(24)11-8-22-17-10(11)6-9(18)7-21-17/h3-4,6-8,23H,2,5H2,1H3,(H,21,22)
• InChIKey: YZDJQTHVDDOVHR-UHFFFAOYSA-N
• PubChem CID: 24180719
• ChEBI ID: CHEBI:90295
• TTD Drug ID: D0J9HW
• DrugBank ID: DB06999

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar blue proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [6]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• In Vitro Model: DBTRG-05MG cells; Brain; Homo sapiens (Human); CVCL_1169
• In Vitro Model: NMC-G1 cells; Brain; Homo sapiens (Human); CVCL_1608
• In Vitro Model: MO59J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: LN405 cells; Brain; Homo sapiens (Human); CVCL_1378
• In Vitro Model: LN172 cells; N.A.; .; N.A.
• In Vitro Model: KG1c cells; Brain; Homo sapiens (Human); CVCL_2971
• In Vitro Model: H4 cells; Brain; Homo sapiens (Human); CVCL_1239
• In Vitro Model: GMS10 cells; Brain; Homo sapiens (Human); CVCL_1233
• In Vitro Model: GAMG cells; Brain; Homo sapiens (Human); CVCL_1226
• In Vitro Model: CCF-STTG1 cells; Brain; Homo sapiens (Human); CVCL_1118
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vitro Model: 8MGBA cells; Brain; Homo sapiens (Human); CVCL_1052
• In Vitro Model: 42MGBA cells; Brain; Homo sapiens (Human); CVCL_1798
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: PLX4720 suppresses MEK-ERK phosphorylation and cell proliferation in MA cells containing BRAFV600E mutation.

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [7]

• 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 PLX4720 by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.F53L (c.157T>C)
• 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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.F53L (c.157T>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• 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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.K57N (c.171G>C)
• 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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.K57N (c.171G>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.I111S (c.332T>G)
• 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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.I111S (c.332T>G) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.C121S (c.361T>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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.F129L (c.385T>C)
• 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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.F129L (c.385T>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]

• Molecule Alteration: Missense mutation; p.V211D (c.632T>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
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.V211D (c.632T>A) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway

Colon cancer [ICD-11: 2B90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

Melanoma [ICD-11: 2C30]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [3]

• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Sanger sequencing assay; SNP array; qPCR
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: MAPK/ERK kinase 1 (MEK1) [4]

• Molecule Alteration: Missense mutation; p.Q56P (c.167A>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.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of PLX4720 by unusual activation of pro-survival pathway

Key Molecule: GTPase Nras (NRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

References

• Ref 1: Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanomaCancer Cell. 2015 Jan 12;27(1):85-96. doi: 10.1016/j.ccell.2014.11.006. Epub 2014 Dec 11.
• Ref 2: Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating CellsCancer Res. 2015 Dec 15;75(24):5355-66. doi: 10.1158/0008-5472.CAN-14-3689. Epub 2015 Nov 16.
• Ref 3: Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibitionAnn Oncol. 2014 May;25(5):959-67. doi: 10.1093/annonc/mdu049. Epub 2014 Feb 6.
• Ref 4: 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 5: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activityProc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. doi: 10.1073/pnas.0711741105. Epub 2008 Feb 19.
• Ref 6: Targeted therapy for BRAFV600E malignant astrocytomaClin Cancer Res. 2011 Dec 15;17(24):7595-604. doi: 10.1158/1078-0432.CCR-11-1456. Epub 2011 Oct 28.
• Ref 7: Gatekeeper mutations mediate resistance to BRAF-targeted therapiesSci Transl Med. 2010 Jun 9;2(35):35ra41. doi: 10.1126/scitranslmed.3000758.
• Ref 8: Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancersBiochim Biophys Acta Proteins Proteom. 2019 Jan;1867(1):62-70. doi: 10.1016/j.bbapap.2018.05.004. Epub 2018 May 9.