Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ZWY32)

• DOT Name: Gasdermin-E (GSDME)
• Synonyms: Inversely correlated with estrogen receptor expression 1; ICERE-1; Non-syndromic hearing impairment protein 5
• Gene Name: GSDME
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss
  Autosomal dominant nonsyndromic hearing loss 1
  Adenocarcinoma
  Advanced cancer
  Autosomal dominant nonsyndromic hearing loss 5
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Intestinal cancer
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Melanoma
  Neoplasm
  Osteosarcoma
  Rheumatoid arthritis
  Schizophrenia
  Squamous cell carcinoma
  Autoimmune disease
  Gastric cancer
  Stomach cancer
  Stroke
  Bipolar disorder
  Sensorineural hearing loss disorder
• UniProt ID: GSDME_HUMAN
• Pfam ID: PF04598 ; PF17708
• Sequence:
  MFAKATRNFLREVDADGDLIAVSNLNDSDKLQLLSLVTKKKRFWCWQRPKYQFLSLTLGD
  VLIEDQFPSPVVVESDFVKYEGKFANHVSGTLETALGKVKLNLGGSSRVESQSSFGTLRK
  QEVDLQQLIRDSAERTINLRNPVLQQVLEGRNEVLCVLTQKITTMQKCVISEHMQVEEKC
  GGIVGIQTKTVQVSATEDGNVTKDSNVVLEIPAATTIAYGVIELYVKLDGQFEFCLLRGK
  QGGFENKKRIDSVYLDPLVFREFAFIDMPDAAHGISSQDGPLSVLKQATLLLERNFHPFA
  ELPEPQQTALSDIFQAVLFDDELLMVLEPVCDDLVSGLSPTVAVLGELKPRQQQDLVAFL
  QLVGCSLQGGCPGPEDAGSKQLFMTAYFLVSALAEMPDSAAALLGTCCKLQIIPTLCHLL
  RALSDDGVSDLEDPTLTPLKDTERFGIVQRLFASADISLERLKSSVKAVILKDSKVFPLL
  LCITLNGLCALGREHS
• Function: [Gasdermin-E]: Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis. This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-E, N-terminal) binds to membranes and forms pores, triggering pyroptosis ; [Gasdermin-E, N-terminal]: Pore-forming protein produced by cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, respectively. After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukins (IL1B and IL16) and triggering pyroptosis. Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate. Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis. Mediates secondary necrosis downstream of the mitochondrial apoptotic pathway and CASP3 activation as well as in response to viral agents. Exhibits bactericidal activity. Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity. Suppresses tumors by mediating granzyme-mediated pyroptosis in target cells of natural killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target cells from NK-cells, triggers pyroptosis of tumor cells and tumor suppression. May play a role in the p53/TP53-regulated cellular response to DNA damage ; [Gasdermin-E, N-terminal]: (Microbial infection) Pore-forming protein, which promotes maternal placental pyroptosis in response to Zika virus infection, contributing to adverse fetal outcomes.
• Tissue Specificity: Expressed in cochlea . Low level of expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas, with highest expression in placenta .
• KEGG Pathway: Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  Pyroptosis (R-HSA-5620971)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  Defective pyroptosis (R-HSA-9710421)
  Release of apoptotic factors from the mitochondria (R-HSA-111457)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 1	DISDZ6CC	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[4]
Autosomal dominant nonsyndromic hearing loss 5	DISZ795Z	Strong	Autosomal dominant	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Intestinal cancer	DISYCNF1	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[13]
Melanoma	DIS1RRCY	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[18]
Autoimmune disease	DISORMTM	moderate	Biomarker	[19]
Gastric cancer	DISXGOUK	moderate	Biomarker	[20]
Stomach cancer	DISKIJSX	moderate	Biomarker	[20]
Stroke	DISX6UHX	moderate	Genetic Variation	[21]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[22]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Biomarker	[23]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Gasdermin-E (GSDME).	[24]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Gasdermin-E (GSDME).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Gasdermin-E (GSDME).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gasdermin-E (GSDME).	[36]

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Gasdermin-E (GSDME).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gasdermin-E (GSDME).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gasdermin-E (GSDME).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Gasdermin-E (GSDME).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gasdermin-E (GSDME).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Gasdermin-E (GSDME).	[30]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Gasdermin-E (GSDME).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Gasdermin-E (GSDME).	[32]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Gasdermin-E (GSDME).	[33]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Gasdermin-E (GSDME).	[34]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Gasdermin-E (GSDME).	[35]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Gasdermin-E (GSDME).	[37]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Gasdermin-E (GSDME).	[33]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Gasdermin-E (GSDME).	[33]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Gasdermin-E (GSDME).	[33]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Gasdermin-E (GSDME).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gasdermin-E (GSDME).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gasdermin-E (GSDME).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gasdermin-E (GSDME).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Gasdermin-E (GSDME).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Gasdermin-E (GSDME).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gasdermin-E (GSDME).	[46]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Gasdermin-E (GSDME).	[47]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin increases the cleavage of Gasdermin-E (GSDME).	[38]
Piperlongumine	DMIZCOE	Preclinical	Piperlongumine increases the cleavage of Gasdermin-E (GSDME).	[44]

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