Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQR6ENW)

• DOT Name: Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)
• Synonyms: EC 2.7.11.25; Apoptosis signal-regulating kinase 1; ASK-1; MAPK/ERK kinase kinase 5; MEK kinase 5; MEKK 5
• Gene Name: MAP3K5
• UniProt ID: M3K5_HUMAN
• PDB ID: 2CLQ; 3VW6; 4BF2; 4BHN; 4BIB; 4BIC; 4BID; 4BIE; 5ULM; 5UOR; 5UOX; 5UP3; 5V19; 5V24; 5VIL; 5VIO; 6E2M; 6E2N; 6E2O; 6EJL; 6OYT; 6OYW; 6VRE; 6XIH; 7MU7
• EC Number: 2.7.11.25
• Pfam ID: PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069
• Sequence:
  MSTEADEGITFSVPPFAPSGFCTIPEGGICRRGGAAAVGEGEEHQLPPPPPGSFWNVESA
  AAPGIGCPAATSSSSATRGRGSSVGGGSRRTTVAYVINEASQGQLVVAESEALQSLREAC
  ETVGATLETLHFGKLDFGETTVLDRFYNADIAVVEMSDAFRQPSLFYHLGVRESFSMANN
  IILYCDTNSDSLQSLKEIICQKNTMCTGNYTFVPYMITPHNKVYCCDSSFMKGLTELMQP
  NFELLLGPICLPLVDRFIQLLKVAQASSSQYFRESILNDIRKARNLYTGKELAAELARIR
  QRVDNIEVLTADIVINLLLSYRDIQDYDSIVKLVETLEKLPTFDLASHHHVKFHYAFALN
  RRNLPGDRAKALDIMIPMVQSEGQVASDMYCLVGRIYKDMFLDSNFTDTESRDHGASWFK
  KAFESEPTLQSGINYAVLLLAAGHQFESSFELRKVGVKLSSLLGKKGNLEKLQSYWEVGF
  FLGASVLANDHMRVIQASEKLFKLKTPAWYLKSIVETILIYKHFVKLTTEQPVAKQELVD
  FWMDFLVEATKTDVTVVRFPVLILEPTKIYQPSYLSINNEVEEKTISIWHVLPDDKKGIH
  EWNFSASSVRGVSISKFEERCCFLYVLHNSDDFQIYFCTELHCKKFFEMVNTITEEKGRS
  TEEGDCESDLLEYDYEYDENGDRVVLGKGTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQ
  PLHEEIALHKHLKHKNIVQYLGSFSENGFIKIFMEQVPGGSLSALLRSKWGPLKDNEQTI
  GFYTKQILEGLKYLHDNQIVHRDIKGDNVLINTYSGVLKISDFGTSKRLAGINPCTETFT
  GTLQYMAPEIIDKGPRGYGKAADIWSLGCTIIEMATGKPPFYELGEPQAAMFKVGMFKVH
  PEIPESMSAEAKAFILKCFEPDPDKRACANDLLVDEFLKVSSKKKKTQPKLSALSAGSNE
  YLRSISLPVPVLVEDTSSSSEYGSVSPDTELKVDPFSFKTRAKSCGERDVKGIRTLFLGI
  PDENFEDHSAPPSPEEKDSGFFMLRKDSERRATLHRILTEDQDKIVRNLMESLAQGAEEP
  KLKWEHITTLIASLREFVRSTDRKIIATTLSKLKLELDFDSHGISQVQVVLFGFQDAVNK
  VLRNHNIKPHWMFALDSIIRKAVQTAITILVPELRPHFSLASESDTADQEDLDVEDDHEE
  QPSNQTVRRPQAVIEDAVATSGVSTLSSTVSHDSQSAHRSLNVQLGRMKIETNRLLEELV
  RKEKELQALLHRAIEEKDQEIKHLKLKSQPIEIPELPVFHLNSSGTNTEDSELTDWLRVN
  GADEDTISRFLAEDYTLLDVLYYVTRDDLKCLRLRGGMLCTLWKAIIDFRNKQT
• Function: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).
• Tissue Specificity: Abundantly expressed in heart and pancreas.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  MAPK sig.ling pathway (hsa04010)
  Sphingolipid sig.ling pathway (hsa04071)
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Tight junction (hsa04530)
  TNF sig.ling pathway (hsa04668)
  Thermogenesis (hsa04714)
  Neurotrophin sig.ling pathway (hsa04722)
  Non-alcoholic fatty liver disease (hsa04932)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway: Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the activity of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the activity of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[10]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[11]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[13]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[14]
Levodopa	DMN3E57	Approved	Levodopa increases the activity of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[19]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[21]
TAK-114	DMTXE19	Phase 1	TAK-114 increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[22]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[27]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[15]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the phosphorylation of Mitogen-activated protein kinase kinase kinase 5 (MAP3K5).	[24]

References

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