Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0368)
Name
ZZW-115
Synonyms
ZZW-115; 801991-87-7; ZZW-115 trihydrochloride; CHEMBL524240; ICI738; SCHEMBL10168901; HUDONDPCYIGAMQ-UHFFFAOYSA-O; EX-A5834; HY-111838; CS-0093153; N,N-Dimethyl-2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethanamine trihydrochloride; N,N-dimethyl-2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanamine

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Structure
Formula
C24H31F3N4S
IUPAC Name
N,N-dimethyl-2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanamine
Canonical SMILES
CN(C)CCN1CCN(CC1)CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F
InChI
InChI=1S/C24H31F3N4S/c1-28(2)12-13-30-16-14-29(15-17-30)10-5-11-31-20-6-3-4-7-22(20)32-23-9-8-19(18-21(23)31)24(25,26)27/h3-4,6-9,18H,5,10-17H2,1-2H3
InChIKey
HUDONDPCYIGAMQ-UHFFFAOYSA-N
PubChem CID
25010688
Full List of Ferroptosis Target Related to This Drug
Unspecific Target
In total 4 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Responsed Regulator Transcription factor A, mitochondrial (TFAM) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
Xenografts with MiaPaCa-2 and HepG2 cells in nude mice and treated them for 4 or 3 weeks, respectively, with vehicle alone and 2.5 or 5.0 mg/kg/day of ZZW-115. Then, we measured the GPX4 activity and analyzed the mRNA levels of the key genes involved in ferroptosis by qRT-PCR analysis.

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Response regulation The expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. These results have been validated in xenografts induced with pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells in nude mice during the treatment with ZZW-115.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Responsed Regulator Nuclear protein 1 (NUPR1) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
Xenografts with MiaPaCa-2 and HepG2 cells in nude mice and treated them for 4 or 3 weeks, respectively, with vehicle alone and 2.5 or 5.0 mg/kg/day of ZZW-115. Then, we measured the GPX4 activity and analyzed the mRNA levels of the key genes involved in ferroptosis by qRT-PCR analysis.

    Click to Show/Hide
Response regulation The expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. These results have been validated in xenografts induced with pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells in nude mice during the treatment with ZZW-115.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Transcription factor A, mitochondrial (TFAM) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
Xenografts with MiaPaCa-2 and HepG2 cells in nude mice and treated them for 4 or 3 weeks, respectively, with vehicle alone and 2.5 or 5.0 mg/kg/day of ZZW-115. Then, we measured the GPX4 activity and analyzed the mRNA levels of the key genes involved in ferroptosis by qRT-PCR analysis.

    Click to Show/Hide
Response regulation The expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. These results have been validated in xenografts induced with pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells in nude mice during the treatment with ZZW-115.
Experiment 4 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Nuclear protein 1 (NUPR1) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
Xenografts with MiaPaCa-2 and HepG2 cells in nude mice and treated them for 4 or 3 weeks, respectively, with vehicle alone and 2.5 or 5.0 mg/kg/day of ZZW-115. Then, we measured the GPX4 activity and analyzed the mRNA levels of the key genes involved in ferroptosis by qRT-PCR analysis.

    Click to Show/Hide
Response regulation The expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. These results have been validated in xenografts induced with pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells in nude mice during the treatment with ZZW-115.
References
Ref 1 NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner. Cell Death Discov. 2021 Oct 1;7(1):269. doi: 10.1038/s41420-021-00662-2.