Drug Information

Drug (ID: DG01612) and It's Reported Resistant Information

• Name: DEBIO-1347
• Synonyms: 1265229-25-1; CH5183284; Debio-1347; zoligratinib; CH-5183284; CH5183284 (Debio-1347); Debio 1347; UNII-NR9ZYH80Z8; FF284; NR9ZYH80Z8; CHEMBL3907479; (5-Amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-4-yl)(1H-indol-2-yl)methanone; [5-Amino-1-(2-Methyl-1h-Benzimidazol-6-Yl)-1h-Pyrazol-4-Yl](1h-Indol-2-Yl)methanone; [5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone; Fgfr inhibitor debio 1347; DEBIO1347; GTPL9787; SCHEMBL10002991; HMS3674G21; HMS3748K13; BCP14354; EX-A1122; BDBM50197683; MFCD28502053; NSC782363; NSC800074; s7665; ZINC98209140; AKOS027427006; CH5183284; Debio-1347; CCG-264725; CS-5504; DB12903; NSC-782363; NSC-800074; SB16908; Methanone, (5-amino-1-(2-methyl-1H-benzimidazol-6-yl)-1H-pyrazol-4-yl)-1H-indol-2-yl-; NCGC00386433-01; AC-32960; BS-14797; HY-19957; CH 5183284; J3.616.632K; A14415; A901067; Q27285013; (5-amino-1-(2-methyl-3H-benzo[d]imidazol-5-yl)-1H-pyrazol-4-yl)(1H-indol-2-yl)methanone; [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl) methanone; [5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone; [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)methanone; [5-amino-1-(2-methyl-3h-benzimidazol-5-yl)pyrazol-4-yl](1h-indol-2-yl)methanone; 1-(2-Methyl-1H-benzoimidazole-6-yl)-4-(1H-indole-2-ylcarbonyl)-1H-pyrazole-5-amine; LWJ
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [1]
• Target: Enhancer of zeste homolog 2 (EZH2); EZH2_HUMAN; [2]
• Formula: 3
• IsoSMILES: CC1=NC2=C(N1)C=C(C=C2)N3C(=C(C=N3)C(=O)C4=CC5=CC=CC=C5N4)N
• InChI: InChI=1S/C20H16N6O/c1-11-23-16-7-6-13(9-17(16)24-11)26-20(21)14(10-22-26)19(27)18-8-12-4-2-3-5-15(12)25-18/h2-10,25H,21H2,1H3,(H,23,24)
• InChIKey: BEMNJULZEQTDJY-UHFFFAOYSA-N
• PubChem CID: 66555680
• TTD Drug ID: D02BBA
• DrugBank ID: DB12903

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [2]

• Molecule Alteration: Missense mutation; p.V564I (c.1690G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [2]

• Molecule Alteration: Missense mutation; p.V564L (c.1690G>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Molecule Alteration: Missense mutation; p.N540K (c.1620C>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gallbladder; N.A.
• Experiment for Molecule Alteration: Targeted sequencing of tumor tissue assay
• Mechanism Description: The missense mutation p.N540K (c.1620C>G) in gene FGFR3 cause the resistance of DEBIO-1347 by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Molecule Alteration: Missense mutation; p.V555M (c.1663G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gallbladder; N.A.
• Experiment for Molecule Alteration: Targeted sequencing of tumor tissue assay
• Mechanism Description: The missense mutation p.V555M (c.1663G>A) in gene FGFR3 cause the resistance of DEBIO-1347 by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Molecule Alteration: Missense mutation; p.L608V (c.1822T>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gallbladder; N.A.
• Experiment for Molecule Alteration: Targeted sequencing of tumor tissue assay
• Mechanism Description: The missense mutation p.L608V (c.1822T>G) in gene FGFR3 cause the resistance of DEBIO-1347 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [2]

• Molecule Alteration: Missense mutation; p.V564F (c.1690G>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gallbladder; N.A.
• Experiment for Molecule Alteration: Targeted sequencing of tumor tissue assay
• Mechanism Description: The missense mutation p.K650E (c.1948A>G) in gene FGFR3 cause the sensitivity of DEBIO-1347 by aberration of the drug's therapeutic target

Myeloproliferative neoplasm [ICD-11: 2A22]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [2]

• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [2]

• Molecule Alteration: Missense mutation; p.F386L (c.1156T>C)
• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [2]

• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Endometrial cancer [ICD-11: 2C76]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [2]

• Molecule Alteration: Missense mutation; p.S252W (c.755C>G)
• Sensitive Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [2]

• Molecule Alteration: Missense mutation; p.N549K (c.1647T>G)
• Sensitive Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Bladder cancer [ICD-11: 2C94]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [2]

• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [3]

• Molecule Alteration: Synonymous; p.K650K (c.1950G>A)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [3]

• Molecule Alteration: Missense mutation; p.S371C (c.1111A>T)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [3]

• Molecule Alteration: Missense mutation; p.G380R (c.1138G>A)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data

References

• Ref 1: Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive CholangiocarcinomaCancer Discov. 2017 Mar;7(3):252-263. doi: 10.1158/2159-8290.CD-16-1000. Epub 2016 Dec 29.
• Ref 2: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitorMol Cancer Ther. 2014 Nov;13(11):2547-58. doi: 10.1158/1535-7163.MCT-14-0248. Epub 2014 Aug 28.
• Ref 3: Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivoBr J Cancer. 2011 Jan 4;104(1):75-82. doi: 10.1038/sj.bjc.6606016. Epub 2010 Nov 30.
• Ref 4: A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene AlterationsClin Cancer Res. 2019 May 1;25(9):2699-2707. doi: 10.1158/1078-0432.CCR-18-1959. Epub 2019 Feb 11.