Drug Information

Drug (ID: DG01656) and It's Reported Resistant Information
Name
Lazertinib
Synonyms
Lazertinib; 1903008-80-9; GNS-1480; YH25448; YH-25448; GNS1480; JNJ-73841937-AAA; UNII-4A2Y23XK11; N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide; C-18112003-G; 4A2Y23XK11; N-(5-((4-(4-((Dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide; Leclaza; Lazertinib [USAN]; Lazertinib [INN]; Lazertinib (YH25448); CHEMBL4558324; SCHEMBL17670400; GTPL10136; BCP30440; EX-A1912; BDBM50555575; s8724; WHO 10587; AKOS037515597; CCG-270023; Lazertinib (YH25448,GNS-1480); YH-25448;GNS-1480; BS-15742; Compound 73 [WO2016060443A2]; HY-109061; CS-0032992; A16827; A903188; YH-25448; YH 25448; YH25448; GNS-1480; GNS 1480; GNS1480; 2-Propenamide, N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-2-pyrimidinyl)amino)-4-methoxy-2-(4-morpholinyl)phenyl)-; N-(5-((4-(4-((Dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-2-pyrimidinyl)amino)-4-methoxy-2-(4-morpholinyl)phenyl)acrylamide; N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide
    Click to Show/Hide
Indication
In total 1 Indication(s)
Non-small-cell lung cancer [ICD-11: 2C25]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Lung cancer [ICD-11: 2C25]
[2]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
10
IsoSMILES
CN(C)CC1=CN(N=C1C2=CC=CC=C2)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N5CCOCC5)OC
InChI
InChI=1S/C30H34N8O3/c1-5-28(39)32-23-17-24(26(40-4)18-25(23)37-13-15-41-16-14-37)33-30-31-12-11-27(34-30)38-20-22(19-36(2)3)29(35-38)21-9-7-6-8-10-21/h5-12,17-18,20H,1,13-16,19H2,2-4H3,(H,32,39)(H,31,33,34)
InChIKey
RRMJMHOQSALEJJ-UHFFFAOYSA-N
PubChem CID
121269225
DrugBank ID
DB16216
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
Click to Show/Hide the Resistance Disease of This Class
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
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]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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870
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880
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890
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1020
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
H2291 cells Lung Homo sapiens (Human) CVCL_1546
In Vivo Model Female BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay
Experiment for
Drug Resistance		 Cell-free kinase assay; IC50 assay
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase UFO (AXL) [2]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ERK signaling pathway Activation hsa04210
AKT signaling pathway Regulation N.A.
In Vitro Model HCC4011 cells Lung Homo sapiens (Human) N.A.
NCI-H1975 EGFR-T790M/C797S/L858R cells Lung Homo sapiens (Human) CVCL_UE30
HCC827 cells Lung Homo sapiens (Human) CVCL_2063
HCC4006 cells Lung Homo sapiens (Human) CVCL_1269
PC-9 cells Lung Homo sapiens (Human) CVCL_B260
Experiment for
Molecule Alteration		 Western blot assay; RT-PCR
Mechanism Description This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.
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]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L858R (c.2573T>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.64  Å
PDB: 4LI5
Mutant Type Structure Method: X-ray diffraction Resolution: 2.47  Å
PDB: 2ITV
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.34
TM score: 0.90001
Amino acid change:
L858R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
S
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M
-
G
G
E
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700
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710
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720
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730
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780
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790
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800
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810
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820
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880
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890
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900
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910
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930
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950
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970
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980
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990
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1010
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Y
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L
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1020
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Q
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-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
H2291 cells Lung Homo sapiens (Human) CVCL_1546
In Vivo Model Female BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay
Experiment for
Drug Resistance		 Cell-free kinase assay; IC50 assay
Key Molecule: Epidermal growth factor receptor (EGFR) [1]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.L861Q (c.2582T>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC9 cells Lung Homo sapiens (Human) CVCL_B260
PC9GR cells Lung Homo sapiens (Human) CVCL_V337
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
H2291 cells Lung Homo sapiens (Human) CVCL_1546
In Vivo Model Female BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Sanger sequencing assay
Experiment for
Drug Resistance		 Cell-free kinase assay; IC50 assay
References
Ref 1 YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung CancerClin Cancer Res. 2019 Apr 15;25(8):2575-2587. doi: 10.1158/1078-0432.CCR-18-2906. Epub 2019 Jan 22.
Ref 2 Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells. Cancer Sci. 2024 Oct;115(10):3333-3345.

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