Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0287)
Name
Siramesine
Synonyms
Siramesine; 147817-50-3; Siramesine [INN]; 1'-(4-(1-(4-fluorophenyl)-1H-indol-3-yl)butyl)-3H-spiro[isobenzofuran-1,4'-piperidine]; Lu 28-179; Lu-28-179; 3IX8CWR24V; CHEMBL61479; 1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]; UNII-3IX8CWR24V; Siramesine(Lu 28-179); SCHEMBL2090079; DTXSID90163810; EX-A355; XWAONOGAGZNUSF-UHFFFAOYSA-N; BCP08745; BDBM50035105; AKOS027251054; CS-1920; DB06555; Spiro[isobenzofuran-1(3H),4'-piperidine], 1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-; NCGC00370727-06; HY-14221; A13036; A857438; Q7529961; 1'-(4-(1-(p-Fluorophenyl)indol-3-yl)butyl)spiro(phthalan-1,4'-piperidine); Lu-28-179; Lu 28-179; Lu28-179; Lu-28179; Lu 28179; Lu28179; 1''-{4-[1-(4-fluorophenyl)-1H-3-indolyl]butyl}spiro[1,3-dihydroisobenzofuran-1,4''-(hexahydropyridine)]; 1''-{4-[1-(4-fluorophenyl)-1H-3-indolyl]butyl}spiro[1,3-dihydroisobenzofuran-1,4''-(hexahydropyridine)](Lu 28-179); 1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine]

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Status
Terminated
Drug Type
Small molecular drug
Structure
Formula
C30H31FN2O
IUPAC Name
1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]
Canonical SMILES
C1CN(CCC12C3=CC=CC=C3CO2)CCCCC4=CN(C5=CC=CC=C54)C6=CC=C(C=C6)F
InChI
InChI=1S/C30H31FN2O/c31-25-12-14-26(15-13-25)33-21-23(27-9-2-4-11-29(27)33)7-5-6-18-32-19-16-30(17-20-32)28-10-3-1-8-24(28)22-34-30/h1-4,8-15,21H,5-7,16-20,22H2
InChIKey
XWAONOGAGZNUSF-UHFFFAOYSA-N
PubChem CID
9829526
TTD Drug ID
D0XK2K
Full List of Ferroptosis Target Related to This Drug
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 [1]
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 [2]
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 [3]
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 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 2 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 3 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.