Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFHOD0C)

• DOT Name: Kelch-like ECH-associated protein 1 (KEAP1)
• Synonyms: Cytosolic inhibitor of Nrf2; INrf2; Kelch-like protein 19
• Gene Name: KEAP1
• Related Disease: Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors
• UniProt ID: KEAP1_HUMAN
• PDB ID: 1U6D ; 1ZGK ; 2FLU ; 3VNG ; 3VNH ; 3ZGC ; 3ZGD ; 4CXI ; 4CXJ ; 4CXT ; 4IFJ ; 4IFL ; 4IFN ; 4IN4 ; 4IQK ; 4L7B ; 4L7C ; 4L7D ; 4N1B ; 4XMB ; 5DAD ; 5DAF ; 5F72 ; 5GIT ; 5NLB ; 5WFL ; 5WFV ; 5WG1 ; 5WHL ; 5WHO ; 5WIY ; 5X54 ; 6FFM ; 6FMP ; 6FMQ ; 6HWS ; 6LRZ ; 6ROG ; 6SP1 ; 6SP4 ; 6T7V ; 6T7Z ; 6TG8 ; 6TYM ; 6TYP ; 6UF0 ; 6V6Z ; 6W66 ; 6W67 ; 6W68 ; 6W69 ; 6WCQ ; 6Z6A ; 7EXI ; 7K28 ; 7K29 ; 7K2A ; 7K2B ; 7K2C ; 7K2D ; 7K2E ; 7K2F ; 7K2G ; 7K2H ; 7K2I ; 7K2J ; 7K2K ; 7K2L ; 7K2M ; 7K2N ; 7K2O ; 7K2P ; 7K2Q ; 7K2R ; 7K2S ; 7Q5H ; 7Q6Q ; 7Q6S ; 7Q8R ; 7Q96 ; 7X4W ; 7X4X ; 7XM2 ; 7XM3 ; 7XM4 ; 7XM5 ; 7XOT ; 8EHV ; 8EJR ; 8EJS ; 8IVG ; 8IVR ; 8IXS ; 8PKU ; 8PKV ; 8PKW ; 8PKX ; 8WFG ; 8X34
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHT
  KQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGM
  EVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLD
  PSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVR
  CESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDY
  LVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQV
  PRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGV
  IDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDG
  TNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVE
  TETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSG
  RSGVGVAVTMEPCRKQIDQQNCTC
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome.
• Tissue Specificity: Broadly expressed, with highest levels in skeletal muscle.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Parkinson disease (hsa05012)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Hepatocellular carcinoma (hsa05225)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Potential therapeutics for SARS (R-HSA-9679191)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Nuclear events mediated by NFE2L2 (R-HSA-9759194)
  Antigen processing (R-HSA-983168)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors	DISVJILV	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Kelch-like ECH-associated protein 1 (KEAP1) affects the response to substance of Fluorouracil.	[38]
Etoposide	DMNH3PG	Approved	Kelch-like ECH-associated protein 1 (KEAP1) increases the response to substance of Etoposide.	[39]

45 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 Kelch-like ECH-associated protein 1 (KEAP1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[11]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[3]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[13]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[14]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[16]
Trabectedin	DMG3Y89	Approved	Trabectedin increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[19]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[20]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[21]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[21]
Triptolide	DMCMDVR	Phase 3	Triptolide decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[23]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[30]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[32]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[33]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[34]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[24]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[35]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[24]
ROSMARINIC ACID	DMQ6SJT	Investigative	ROSMARINIC ACID decreases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[13]
THIOCTIC ACID	DMNFCXW	Investigative	THIOCTIC ACID increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[24]
Iodoacetamide	DMM4XVL	Investigative	Iodoacetamide increases the expression of Kelch-like ECH-associated protein 1 (KEAP1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Kelch-like ECH-associated protein 1 (KEAP1).	[15]
Hesperetin	DMKER83	Approved	Hesperetin affects the binding of Kelch-like ECH-associated protein 1 (KEAP1).	[17]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR affects the binding of Kelch-like ECH-associated protein 1 (KEAP1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the ubiquitination of Kelch-like ECH-associated protein 1 (KEAP1).	[37]

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