Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0084)
Name
Lapatinib
Synonyms
Lapatinib; 231277-92-2; Tykerb; GW572016; GW 572016; Lapatinib [INN]; Lapatinib base; Tyverb; 388082-78-8; Lapatinib (INN); Lapatinib free base; N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-amine; N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine; N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazolin-4-amine; Lapatinib (free base); 231277-92-2 (free base); GSK572016; FMM; N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE; CHEMBL554; GW-572016; DTXSID7046675; CHEBI:49603; 0VUA21238F; NSC745750; GSK-572016; GW-572016X; 1210608-87-9; NCGC00167507-01; N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine; DTXCID5026675; 4-Quinazolinamine, N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl)-; 4-Quinazolinamine, N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-; N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl)-4-quinazolinamine; N-(3-Chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-((2-methylsulfonylethylamino)methyl)-2-furyl)quinazolin-4-amine; n-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine; N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-amine; GSK 572016; CAS-231277-92-2; GW-2016; Lapatinib [INN:BAN]; MFCD09264194; GW 282974X; C29H26ClFN4O4S; UNII-0VUA21238F; HSDB 8209; 1xkk; Lapatinib, Tykerb, GW572016; N-[3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; Lapatinib, Free base; nchembio866-comp20; Kinome_3684; Kinome_3685; Lapatinib base- Bio-X; LAPATINIB [MI]; LAPATINIB [VANDF]; LAPATINIB [WHO-DD]; SCHEMBL8100; Lapatinib (GW572016); LAPATINIB [EMA EPAR]; BDBM5445; cid_208908; GTPL5692; EX-A402; BCFGMOOMADDAQU-UHFFFAOYSA-N; BCPP000188; BCPP000189; HMS2089H10; HMS3244N06; HMS3244N10; HMS3244N14; HMS3744K11; Tykerb (TN) (Glaxo Smith Kline); BCP01874; Tox21_112505; NSC800780; AKOS005145766; Tox21_112505_1; AC-1314; BCP9000837; BCP9000838; CCG-270133; DB01259; NSC-745750; NSC-800780; SB16918; NCGC00167507-02; NCGC00167507-03; NCGC00167507-04; NCGC00167507-09; 913989-15-8; AS-14065; BC164610; HY-50898; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine; N-(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine; AM20090641; FT-0659650; L0360; SW199101-5; A25184; D08108; EN300-117254; AB01273965-01; AB01273965-02; AB01273965-03; AB01273965_04; AB01273965_05; Q420323; Q-101353; SR-05000001472-1; BRD-K19687926-001-01-7; BRD-K19687926-379-02-5; 1092929-10-6; GW-2016;N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-amine;4-[[3-Chloro-4-(3-fluorobenzyloxy)phenyl]amino]-6-[5-[[(2-methanesulfonylethyl)amino]methyl]furan-2-yl]quinazoline; N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-amine; N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine; N-{3-chloro-4-[(3-fluoro-benzyl)oxy]phenyl}-6-[5-({2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methane sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; N-{3-Chloro-4[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methane sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; N3-Chloro-4-(3-fluorophenyl)methoxyphenyl-6-5-(2-methylsulfonylethylamino)methyl-2-furylquinazolin-4-amine

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Structure
Formula
C29H26ClFN4O4S
IUPAC Name
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine
Canonical SMILES
CS(=O)(=O)CCNCC1=CC=C(O1)C2=CC3=C(C=C2)N=CN=C3NC4=CC(=C(C=C4)OCC5=CC(=CC=C5)F)Cl
InChI
InChI=1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
InChIKey
BCFGMOOMADDAQU-UHFFFAOYSA-N
PubChem CID
208908
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 3 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Regulator Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) Suppressor
 Regulator Info 
Pathway Response PI3K-Akt signaling pathway hsa04151
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation Lapatinib (LAP) inhibited the cell viability and exacerbated cell injury induced by doxorubicin, as well as increased cell apoptosis. LAP aggravated Dox-induced cardiotoxicity by promoting oxidative stress and ferroptosis in cardiomyocytes via PI3K/AKT-mediated mitochondrial dysfunction. Moreover, GPX4 expression was decreased and ASCL4 level was higher following DOX treatment or the combination therapy of LAP and DOX.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Regulator RAC-alpha serine/threonine-protein kinase (AKT1) Suppressor
 Regulator Info 
Pathway Response PI3K-Akt signaling pathway hsa04151
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation Lapatinib (LAP) inhibited the cell viability and exacerbated cell injury induced by doxorubicin, as well as increased cell apoptosis. LAP aggravated Dox-induced cardiotoxicity by promoting oxidative stress and ferroptosis in cardiomyocytes via PI3K/AKT-mediated mitochondrial dysfunction. Moreover, GPX4 expression was decreased and ASCL4 level was higher following DOX treatment or the combination therapy of LAP and DOX.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Status epilepticus ICD-11: 8A66
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model HT22 cells Normal Mus musculus CVCL_0321
In Vivo Model
Male C57BL/6J mice (6-8 weeks of age, weighing 18-22 g) were obtained from the Animal Unit of Central South University. After anesthetization by intraperitoneal injection of 10% chloral hydrate (v/w), the mice were fixed on a stereotactic instrument and stereotactically injected with KA (250 ng/ul) into the hippocampus. KA (1 ul) was injected slowly for 5 min and positioned in the hippocampus (AP-2.0 mm, ML-1.3 mm, V-1.2 mm). After injection, the needle was left in place for additional 10 min to avoid drug reflux. The mice were randomly divided into six experimental groups: 1) sham operation group that received 1 ul PBS injection (5 animals); 2) mice were pretreated p. o. for 21 days on a twice-daily schedule with 100 mg/kg lapatinib alone before PBS administration (5 animals); 3) KA-treated group was injected KA (5 animals); 4) and 5) lapatinib groups were received with 50 mg/kg (5 animals) and 100 mg/kg (5 animals) lapatinib for 21 days before KA treatment, respectively; 6) this group was given i. p. for 14 days with ferroptosis inhibitor (3 mg/kg Fer-1) before KA administration.

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Response regulation Lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis.
Solute carrier family 40 member 1 (SLC40A1)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
ZR-75-1 cells Invasive breast carcinoma Homo sapiens CVCL_0588
Response regulation Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.
Heme oxygenase 1 (HMOX1)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Driver/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Response regulation Lapatinib and siramesine was the most effective tyrosine kinase inhibitor and lysosome disruptor drug combination in inducing synergistic cell death in A549 and U87 cells. This cell death was through ferroptosis mediated by ROS and reduced expression of HO-1 in glioma cells.
Unspecific Target
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
Response regulation The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells mediated by ferroptosis. Siramesine and lapatinib initially induced ferroptosis but changes to an autophagy induced cell death after 24 hours.
References
Ref 1 Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway. Bioengineered. 2022 Jan;13(1):48-60. doi: 10.1080/21655979.2021.2004980.
Ref 2 Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016 Jul 21;7(7):e2307. doi: 10.1038/cddis.2016.208.
Ref 3 Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis. Front Pharmacol. 2020 Dec 10;11:601572. doi: 10.3389/fphar.2020.601572. eCollection 2020.
Ref 4 Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels. Oxid Med Cell Longev. 2019 Sep 17;2019:9561281. doi: 10.1155/2019/9561281. eCollection 2019.
Ref 5 Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS One. 2017 Aug 21;12(8):e0182921. doi: 10.1371/journal.pone.0182921. eCollection 2017.