Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDSLC81)

• DOT Name: Mixed lineage kinase domain-like protein (MLKL)
• Synonyms: hMLKL
• Gene Name: MLKL
• Related Disease:
  Adult lymphoma
  Alzheimer disease
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Autoimmune disease
  Autoimmune hepatitis
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Coronary heart disease
  Dilated cardiomyopathy 1A
  Fatty liver disease
  Glioma
  Hepatitis
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Lymphoma
  Myelodysplastic syndrome
  Myocardial infarction
  Neoplasm
  Non-small-cell lung cancer
  Parkinson disease
  Pediatric lymphoma
  Periodontitis
  Pneumonia
  Pneumonitis
  Renal fibrosis
  Squamous cell carcinoma
  Status epilepticus seizure
  Systemic lupus erythematosus
  Tuberculosis
  Ulcerative colitis
  Bacterial infection
  Melanoma
  Stroke
  Asthma
  Advanced cancer
  Gastric cancer
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Obesity
  Stomach cancer
• UniProt ID: MLKL_HUMAN
• PDB ID: 2MSV; 4M67; 4MWI; 5KNJ; 5KO1; 6BWK; 6D74; 6LK5; 6LK6; 6O5Z; 6UX8; 6ZLE; 6ZPR; 6ZVO; 6ZZ1; 7JW7; 7JXU; 7MON; 7NM2; 7NM4; 7NM5; 8SLZ
• Pfam ID: PF07714
• Sequence:
  MENLKHIITLGQVIHKRCEEMKYCKKQCRRLGHRVLGLIKPLEMLQDQGKRSVPSEKLTT
  AMNRFKAALEEANGEIEKFSNRSNICRFLTASQDKILFKDVNRKLSDVWKELSLLLQVEQ
  RMPVSPISQGASWAQEDQQDADEDRRAFQMLRRDNEKIEASLRRLEINMKEIKETLRQYL
  PPKCMQEIPQEQIKEIKKEQLSGSPWILLRENEVSTLYKGEYHRAPVAIKVFKKLQAGSI
  AIVRQTFNKEIKTMKKFESPNILRIFGICIDETVTPPQFSIVMEYCELGTLRELLDREKD
  LTLGKRMVLVLGAARGLYRLHHSEAPELHGKIRSSNFLVTQGYQVKLAGFELRKTQTSMS
  LGTTREKTDRVKSTAYLSPQELEDVFYQYDVKSEIYSFGIVLWEIATGDIPFQGCNSEKI
  RKLVAVKRQQEPLGEDCPSELREIIDECRAHDPSVRPSVDEILKKLSTFSK
• Function: Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process. Does not have protein kinase activity. Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol. Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function.
• KEGG Pathway:
  Necroptosis (hsa04217)
  Cytosolic D.-sensing pathway (hsa04623)
  TNF sig.ling pathway (hsa04668)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  Regulation of necroptotic cell death (R-HSA-5675482)
  Microbial modulation of RIPK1-mediated regulated necrosis (R-HSA-9686347)
  TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Arthritis	DIST1YEL	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[5]
Autoimmune hepatitis	DISOX03Q	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[10]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[10]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[10]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Hepatitis	DISXXX35	Strong	Altered Expression	[6]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[15]
Myocardial infarction	DIS655KI	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Parkinson disease	DISQVHKL	Strong	Biomarker	[18]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[1]
Periodontitis	DISI9JOI	Strong	Biomarker	[19]
Pneumonia	DIS8EF3M	Strong	Biomarker	[20]
Pneumonitis	DIS88E0K	Strong	Biomarker	[21]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[22]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[23]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[24]
Tuberculosis	DIS2YIMD	Strong	Posttranslational Modification	[25]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[26]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[27]
Melanoma	DIS1RRCY	moderate	Biomarker	[28]
Stroke	DISX6UHX	moderate	Biomarker	[29]
Asthma	DISW9QNS	Disputed	Biomarker	[30]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[31]
Gastric cancer	DISXGOUK	Limited	Biomarker	[32]
Non-alcoholic fatty liver disease	DISDG1NL	Limited	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[33]
Obesity	DIS47Y1K	Limited	Biomarker	[33]
Stomach cancer	DISKIJSX	Limited	Biomarker	[32]

24 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 Mixed lineage kinase domain-like protein (MLKL).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[37]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Mixed lineage kinase domain-like protein (MLKL).	[39]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[40]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[42]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mixed lineage kinase domain-like protein (MLKL).	[39]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[43]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[44]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[46]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[47]
Atazanavir	DMSYRBX	Approved	Atazanavir increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[47]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[48]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[49]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[50]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[51]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[52]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[54]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Mixed lineage kinase domain-like protein (MLKL).	[52]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mixed lineage kinase domain-like protein (MLKL).	[55]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[56]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Mixed lineage kinase domain-like protein (MLKL).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the phosphorylation of Mixed lineage kinase domain-like protein (MLKL).	[41]
Ethanol	DMDRQZU	Approved	Ethanol increases the phosphorylation of Mixed lineage kinase domain-like protein (MLKL).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mixed lineage kinase domain-like protein (MLKL).	[53]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the phosphorylation of Mixed lineage kinase domain-like protein (MLKL).	[57]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
CHLORANIL	DMCHGF1	Investigative	CHLORANIL affects the localization of Mixed lineage kinase domain-like protein (MLKL).	[58]

References

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