Drug Information

Drug (ID: DG01594) and It's Reported Resistant Information

• Name: AZD-4547
• Synonyms: AZD4547; 1035270-39-3; AZD-4547; AZD 4547; UNII-2167OG1EKJ; N-(5-(3,5-dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzamide; 2167OG1EKJ; CHEBI:63453; rel-N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]benzamide; N-{3-[2-(3,5-Dimethoxyphenyl)ethyl]-1h-Pyrazol-5-Yl}-4-[(3r,5s)-3,5-Dimethylpiperazin-1-Yl]benzamide; N-{5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl}-4-(cis-3,5-dimethylpiperazin-1-yl)benzamide; N-{5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl}-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide; 66T; KB-74810; N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide; SCHEMBL63884; N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-rel-3,5-dimethylpiperazin-1-yl)benzamide; GTPL7707; QCR-89; SCHEMBL15250892; DTXSID80145887; AMY16612; AOB87745; EX-A1578; 2240AH; MFCD22580423; NSC764239; NSC765338; NSC799346; s2801; ZINC95616598; AKOS024464898; BCP9000364; CCG-269382; CS-0971; DB12247; NSC-764239; NSC-765338; NSC-799346; NCGC00346713-01; NCGC00346713-05; AC-28442; AS-17054; HY-13330; rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide; SW219341-1; J-000994; J-524217; Q27074746; N-(5-(3,5-dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide, rel-; N-(5-(3,5-Dimethoxyphenethyl)-4H-pyrazol-3-yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzamide; N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-Benzamide; N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide; N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin -1-yl]benzamide; N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide
• Indication:
  In total 2 Indication(s)
  Gastric adenocarcinoma [ICD-11: 2B72]; Phase 2/3; [1]
  HER2-positive breast cancer [ICD-11: 2C60-2C6Y]; Phase 2/3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Lung cancer [ICD-11: 2C25]; [2]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Endometrial cancer [ICD-11: 2C76]; [4]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [1]
• Target: Erbb2 tyrosine kinase receptor (HER2); ERBB2_HUMAN; [2]
• Formula: 8
• IsoSMILES: C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC
• InChI: InChI=1S/C26H33N5O3/c1-17-15-31(16-18(2)27-17)22-9-6-20(7-10-22)26(32)28-25-13-21(29-30-25)8-5-19-11-23(33-3)14-24(12-19)34-4/h6-7,9-14,17-18,27H,5,8,15-16H2,1-4H3,(H2,28,29,30,32)/t17-,18+
• InChIKey: VRQMAABPASPXMW-HDICACEKSA-N
• PubChem CID: 51039095
• ChEBI ID: CHEBI:63453
• TTD Drug ID: D09GRX
• DrugBank ID: DB12247

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 Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [5]

• Molecule Alteration: Missense mutation; p.V564F (c.1690G>T)
• 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) [3]

• 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 AZD-4547 by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Promega assay

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

• 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 AZD-4547 by aberration of the drug's therapeutic target

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: Revealed Based on the Cell Line Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Promega assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [6]

• Molecule Alteration: Missense mutation; p.W290C (c.870G>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.W290C (c.870G>T) in gene FGFR2 cause the sensitivity of AZD-4547 by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [6]

• Molecule Alteration: Missense mutation; p.K660E (c.1978A>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.K660E (c.1978A>G) in gene FGFR2 cause the sensitivity of AZD-4547 by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [6]

• Molecule Alteration: Missense mutation; p.K660N (c.1980G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.K660N (c.1980G>C) in gene FGFR2 cause the sensitivity of AZD-4547 by aberration of the drug's therapeutic target

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [2]

• Molecule Alteration: Missense mutation; p.V561M (c.1681G>A)
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: L6 cells; Skeletal muscle; Rattus norvegicus (Rat); CVCL_0385
• In Vitro Model: H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Transwell migration assay; Matrigel invasion assay; Proliferation assay; MTT assay
• Mechanism Description: The V561M mutation biases cells towards a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion and anchorage-independent growth, which was confirmed using CyTOF, a novel single cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1 driven drug resistance in the clinic.

Endometrial cancer [ICD-11: 2C76]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [4]

• Molecule Alteration: Missense mutation; p.S252W (c.755C>G)
• Resistant Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MOLM-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2188
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vivo Model: Female balb/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Phospho-kinase array analysis; Reporter gene assay; Microarray analysis; RT-PCR; Gene set enrichment analysis
• Experiment for Drug Resistance: MTT assay; Soft-agar colony assay

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [4]

• Molecule Alteration: Missense mutation; p.N550K (c.1650T>G)
• Resistant Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MOLM-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2188
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vivo Model: Female balb/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Phospho-kinase array analysis; Reporter gene assay; Microarray analysis; RT-PCR; Gene set enrichment analysis
• Experiment for Drug Resistance: MTT assay; Soft-agar colony 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) [7]

• 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

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [8]

• 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) [7]

• 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) [7]

• 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) [7]

• 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) [8]

• 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) [8]

• 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

Urinary system cancer [ICD-11: 2C95]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [9]

• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Disease: Urinary system cancer [ICD-11: 2C95.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: UMUC14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SNU16 cells; Ascites; Homo sapiens (Human); CVCL_0076
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: NCI-H2444 cells; Lung; Homo sapiens (Human); CVCL_1552
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Mechanism Description: c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition.

References

• Ref 1: Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical useOncotarget. 2016 Apr 26;7(17):24252-68. doi: 10.18632/oncotarget.8132.
• Ref 2: The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMTMol Cancer Res. 2019 Feb;17(2):532-543. doi: 10.1158/1541-7786.MCR-18-0429. Epub 2018 Sep 26.
• Ref 3: 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 4: Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer CellsMol Cancer Ther. 2015 Oct;14(10):2292-302. doi: 10.1158/1535-7163.MCT-15-0032. Epub 2015 Aug 20.
• Ref 5: 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 6: Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinomaCancer Res. 2013 Aug 15;73(16):5195-205. doi: 10.1158/0008-5472.CAN-12-3950. Epub 2013 Jun 20.
• Ref 7: 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.
• Ref 8: 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 9: c-Myc Alteration Determines the Therapeutic Response to FGFR InhibitorsClin Cancer Res. 2017 Feb 15;23(4):974-984. doi: 10.1158/1078-0432.CCR-15-2448. Epub 2016 Jul 11.