Drug Information

Drug (ID: DG01576) and It's Reported Resistant Information

• Name: Derazantinib
• Synonyms: Derazantinib; 1234356-69-4; ARQ-087; ARQ087; UNII-N9B0H171MJ; N9B0H171MJ; ARQ 087; (6R)-6-(2-fluorophenyl)-N-(3-{2-[(2-methoxyethyl)amino]ethyl}phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine; Benzo[h]quinazolin-2-amine, 6-(2-fluorophenyl)-5,6-dihydro-N-[3-[2-[(2-methoxyethyl)amino]ethyl]phenyl]-, (6R)-; Benzo(H)quinazolin-2-amine, 6-(2-fluorophenyl)-5,6-dihydro-N-(3-(2-((2-methoxyethyl)amino)ethyl)phenyl)-, (6R)-; Derazantinib [USAN]; Derazantinib(ARQ-087); Derazantinib (ARQ 087); GTPL9785; CHEMBL4297187; SCHEMBL13273847; ARQ-087ARQ-087; AMY16754; BCP29103; EX-A1717; s8609; WHO 10488; AKOS037648596; CS-7922; DB14889; AC-30343; BS-14785; HY-19981; A16825; C71924; (6R)-6-(2-fluorophenyl)-5,6-dihydro-N-[3-[2-[(2-methoxyethyl)amino]ethyl]phenyl]-Benzo[h]quinazolin-2-amine; (R)-6-(2-fluorophenyl)-N-(3-(2-((2-methoxyethyl)amino)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine
• Indication:
  In total 2 Indication(s)
  Breast cancer [ICD-11: 2C60]; Phase 3; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 3; [1]
• Target: Cyclin-dependent kinase 4 (CDK4); CDK4_HUMAN; [1]
• Target: Cyclin-dependent kinase 6 (CDK6); CDK6_HUMAN; [1]
• Formula: 9
• IsoSMILES: COCCNCCC1=CC(=CC=C1)NC2=NC=C3C[C@H](C4=CC=CC=C4C3=N2)C5=CC=CC=C5F
• InChI: InChI=1S/C29H29FN4O/c1-35-16-15-31-14-13-20-7-6-8-22(17-20)33-29-32-19-21-18-26(24-10-4-5-12-27(24)30)23-9-2-3-11-25(23)28(21)34-29/h2-12,17,19,26,31H,13-16,18H2,1H3,(H,32,33,34)/t26-/m1/s1
• InChIKey: KPJDVVCDVBFRMU-AREMUKBSSA-N
• PubChem CID: 46834118
• TTD Drug ID: D05SBO
• DrugBank ID: DB14889

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

Endometrial cancer [ICD-11: 2C76]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]

• 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
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: RT-112 cells; Urinary bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• 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: COS-1 cells; Kidney; Chlorocebus aethiops (Green monkey); CVCL_0223
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2alpha, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [1]

• 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
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: RT-112 cells; Urinary bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• 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: COS-1 cells; Kidney; Chlorocebus aethiops (Green monkey); CVCL_0223
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2alpha, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions.

Bladder cancer [ICD-11: 2C94]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Missense mutation; p.K652E (c.1954A>G)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: RT-112 cells; Urinary bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• 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: COS-1 cells; Kidney; Chlorocebus aethiops (Green monkey); CVCL_0223
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2alpha, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions.

References

• Ref 1: Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR DysregulationPLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. eCollection 2016.