Drug Information

Drug (ID: DG01644) and It's Reported Resistant Information

• Name: PLX8394
• Synonyms: PLX8394; 1393466-87-9; PLX-8394; UNII-J2L7Z273SG; J2L7Z273SG; PLX 8394; (3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide; (R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; GTPL9131; CHEMBL4303729; SCHEMBL15666953; BDBM317826; BCP19619; EX-A1461; PLX 8394;PLX8394; NSC797932; NSC801007; s7965; ZINC144705377; CS-5123; NSC-797932; NSC-801007; US9624213, Compound P-0338; NCGC00483921-01; BP168493; BS-15485; HY-18972; A16840; D83660; A900333; Q27088419; 1-Pyrrolidinesulfonamide, N-(3-((5-(2-cyclopropyl-5-pyrimidinyl)-1H-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-3-fluoro-, (3R)-
• Indication:
  In total 1 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Phase 2; [1]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [2]
• Formula: 7
• IsoSMILES: C1CN(C[C@@H]1F)S(=O)(=O)NC2=C(C(=C(C=C2)F)C(=O)C3=CNC4=C3C=C(C=N4)C5=CN=C(N=C5)C6CC6)F
• InChI: InChI=1S/C25H21F3N6O3S/c26-16-5-6-34(12-16)38(36,37)33-20-4-3-19(27)21(22(20)28)23(35)18-11-32-25-17(18)7-14(8-31-25)15-9-29-24(30-10-15)13-1-2-13/h3-4,7-11,13,16,33H,1-2,5-6,12H2,(H,31,32)/t16-/m1/s1
• InChIKey: YYACLQUDUDXAPA-MRXNPFEDSA-N
• PubChem CID: 90116675
• TTD Drug ID: D28HJI
• DrugBank ID: DB16038

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

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) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Synonymous; p.K601K (c.1803A>G)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Synonymous; p.G464G (c.1392A>T)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G469R (c.1405G>A)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G469V (c.1406G>T)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Synonymous; p.L597L (c.1791A>T)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PRT cells; Brain; Homo sapiens (Human); CVCL_7207
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; AlamarBlue assay; Colony growth assay

Lung cancer [ICD-11: 2C25]

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) [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC364 cells; Lung; Homo sapiens (Human); CVCL_5134
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• In Vitro Model: H1755 cells; Liver; Homo sapiens (Human); CVCL_1492
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1437 cells; Pleural effusion; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. Acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor.

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

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G466V (c.1397G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC364 cells; Lung; Homo sapiens (Human); CVCL_5134
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• In Vitro Model: H1755 cells; Liver; Homo sapiens (Human); CVCL_1492
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1437 cells; Pleural effusion; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. Acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor.

References

• Ref 1: Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitorsPigment Cell Melanoma Res. 2014 May;27(3):479-84. doi: 10.1111/pcmr.12218. Epub 2014 Feb 10.
• Ref 2: Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancerProc Natl Acad Sci U S A. 2016 Nov 22;113(47):13456-13461. doi: 10.1073/pnas.1610456113. Epub 2016 Nov 9.
• Ref 3: RAF inhibitors that evade paradoxical MAPK pathway activationNature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.