Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67RON3)

• DOT Name: Apoptosis-associated speck-like protein containing a CARD (PYCARD)
• Synonyms: hASC; Caspase recruitment domain-containing protein 5; PYD and CARD domain-containing protein; Target of methylation-induced silencing 1
• Gene Name: PYCARD
• Related Disease:
  Colitis
  Large cell carcinoma
  Lung cancer
  Melanoma
  Neoplasm
  Alzheimer disease
  Amyloidosis
  Brain neoplasm
  Breast cancer
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Human papillomavirus infection
  Lung neoplasm
  Malignant mesothelioma
  Nephropathy
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Rheumatoid arthritis
  Schizophrenia
  Stomach cancer
  Stroke
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vulvar squamous intraepithelial lesion
  Adult glioblastoma
  Advanced cancer
  Calcinosis
  Cervical Intraepithelial neoplasia
  Familial tumoral calcinosis
  Heart valve disorder
  Squamous cell carcinoma
  Adenocarcinoma
  Breast carcinoma
  Depression
  Hereditary diffuse gastric adenocarcinoma
  Obesity
• UniProt ID: ASC_HUMAN
• PDB ID: 1UCP; 2KN6; 3J63; 5H8O; 6K99; 6KI0; 6N1H; 7E5B; 7KEU
• Pfam ID: PF00619 ; PF02758
• Sequence:
  MGRARDAILDALENLTAEELKKFKLKLLSVPLREGYGRIPRGALLSMDALDLTDKLVSFY
  LETYGAELTANVLRDMGLQEMAGQLQAATHQGSGAAPAGIQAPPQSAAKPGLHFIDQHRA
  ALIARVTNVEWLLDALYGKVLTDEQYQAVRAEPTNPSKMRKLFSFTPAWNWTCKDLLLQA
  LRESQSYLVEDLERS
• Function: Functions as a key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in innate immune response by acting as an integral adapter in the assembly of various inflammasomes (NLRP1, NLRP2, NLRP3, NLRP6, AIM2 and probably IFI16) which recruit and activate caspase-1 leading to processing and secretion of pro-inflammatory cytokines. Caspase-1-dependent inflammation leads to macrophage pyroptosis, a form of cell death. The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Clustered PYCARD nucleates the formation of caspase-1 filaments through the interaction of their respective CARD domains, acting as a platform for of caspase-1 polymerization. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in RIGI-triggered pro-inflammatory responses and inflammasome activation. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. Modulates host resistance to DNA virus infection, probably by inducing the cleavage of and inactivating CGAS in presence of cytoplasmic double-stranded DNA ; [Isoform 2]: May have a regulating effect on the function as inflammasome adapter; [Isoform 3]: Seems to inhibit inflammasome-mediated maturation of interleukin-1 beta.
• Tissue Specificity: Widely expressed at low levels. Detected in peripheral blood leukocytes, lung, small intestine, spleen, thymus, colon and at lower levels in placenta, liver and kidney. Very low expression in skeletal muscle, heart and brain. Expressed in lung epithelial cells (at protein level) . Detected in the leukemia cell lines HL-60 and U-937, but not in Jurkat T-cell lymphoma and Daudi Burkitt's lymphoma. Detected in the melanoma cell line WM35, but not in WM793. Not detected in HeLa cervical carcinoma cells and MOLT-4 lymphocytic leukemia cells.
• KEGG Pathway:
  Necroptosis (hsa04217)
  NOD-like receptor sig.ling pathway (hsa04621)
  Cytosolic D.-sensing pathway (hsa04623)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Yersinia infection (hsa05135)
  Influenza A (hsa05164)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  The NLRP3 inflammasome (R-HSA-844456)
  The AIM2 inflammasome (R-HSA-844615)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  CLEC7A/inflammasome pathway (R-HSA-5660668)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colitis	DISAF7DD	Definitive	Biomarker	[1]
Large cell carcinoma	DISYMCOF	Definitive	Genetic Variation	[2]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Melanoma	DIS1RRCY	Definitive	Biomarker	[3]
Neoplasm	DISZKGEW	Definitive	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Amyloidosis	DISHTAI2	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[9]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[11]
Colorectal neoplasm	DISR1UCN	Strong	Posttranslational Modification	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[16]
Lung neoplasm	DISVARNB	Strong	Biomarker	[2]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[17]
Nephropathy	DISXWP4P	Strong	Biomarker	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[21]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[22]
Ovarian neoplasm	DISEAFTY	Strong	Posttranslational Modification	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[21]
Schizophrenia	DISSRV2N	Strong	Biomarker	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[12]
Stroke	DISX6UHX	Strong	Biomarker	[24]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[25]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[25]
Vulvar squamous intraepithelial lesion	DISULIZR	Strong	Biomarker	[26]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[27]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[28]
Calcinosis	DISQP4OR	moderate	Biomarker	[29]
Cervical Intraepithelial neoplasia	DISXP757	moderate	Biomarker	[30]
Familial tumoral calcinosis	DISYJZKG	moderate	Biomarker	[29]
Heart valve disorder	DIS84O7T	moderate	Biomarker	[29]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[31]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[20]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Depression	DIS3XJ69	Limited	Biomarker	[32]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[13]
Obesity	DIS47Y1K	Limited	Altered Expression	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[39]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[42]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[43]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[44]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[45]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[46]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[47]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[48]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[49]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[50]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[51]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[53]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[55]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[56]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[57]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[58]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[59]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[60]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[61]
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the expression of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[62]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the methylation of Apoptosis-associated speck-like protein containing a CARD (PYCARD).	[54]

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