Drug Information

Drug (ID: DG01651) and It's Reported Resistant Information
Name
TAS6417
Synonyms
TAS6417; 1661854-97-2; Zipalertinib; TAS-6417; UNII-T4YMU8TW9H; T4YMU8TW9H; (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide; CLN-081; N-[(8S)-4-Amino-6-methyl-5-quinolin-3-yl-8,9-dihydropyrimido[5,4-b]indolizin-8-yl]prop-2-enamide; Zipalertinib [INN]; CLN081; CHEMBL4650281; SCHEMBL16525948; GTPL11889; EX-A3391; NSC812926; s8814; NSC-812926; AS-79368; HY-112299; CS-0044757; D93895; A937514; 2-Propenamide, N-((8S)-4-amino-8,9-dihydro-6-methyl-5-(3-quinolinyl)pyrimido(5,4-b)indolizin-8-yl)-
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Structure
Target . NOUNIPROTAC [1]
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Formula
3
IsoSMILES
CC1=C[C@@H](CN2C1=C(C3=C(N=CN=C32)N)C4=CC5=CC=CC=C5N=C4)NC(=O)C=C
InChI
InChI=1S/C23H20N6O/c1-3-18(30)28-16-8-13(2)21-19(15-9-14-6-4-5-7-17(14)25-10-15)20-22(24)26-12-27-23(20)29(21)11-16/h3-10,12,16H,1,11H2,2H3,(H,28,30)(H2,24,26,27)/t16-/m0/s1
InChIKey
MKCYPWYURWOKST-INIZCTEOSA-N
PubChem CID
117918742
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
Click to Show/Hide the Resistance Disease of This Class
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration IF-insertion
p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.A767_V769 (c.2299_2307)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration IF-insertion
p.D770_N771insG (c.2310_2311insGGT)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.N771_H773 (c.2311_2319)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.P772_H773 (c.2314_2319)
 Molecule Info 
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Lung cancer [ICD-11: 2C25]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration IF-deletion
p.E746_A750delELREA (c.2236_2250del15)
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.A767_V769 (c.2299_2307)
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.S768_D770 (c.2302_2310)
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Molecule Alteration Duplication
p.N771_H773 (c.2311_2319)
 Molecule Info 
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation EGFR signaling pathway Inhibition hsa01521
In Vitro Model HCC827 cells Lung Homo sapiens (Human) CVCL_2063
NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
NCI-H23 cells Lung Homo sapiens (Human) CVCL_1547
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
NCI-H1875 cells N.A. Homo sapiens (Human) N.A.
LXF 2378L cells N.A. . N.A.
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
References
Ref 1 TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion MutationsMol Cancer Ther. 2018 Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10.

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