Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJX38T)

• DOT Name: Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3)
• Synonyms: EC 2.7.11.1; Germinal center kinase-related protein kinase; GLK; MAPK/ERK kinase kinase kinase 3; MEK kinase kinase 3; MEKKK 3
• Gene Name: MAP4K3
• UniProt ID: M4K3_HUMAN
• PDB ID: 5J5T
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00069
• Sequence:
  MNPGFDLSRRNPQEDFELIQRIGSGTYGDVYKARNVNTGELAAIKVIKLEPGEDFAVVQQ
  EIIMMKDCKHPNIVAYFGSYLRRDKLWICMEFCGGGSLQDIYHVTGPLSELQIAYVSRET
  LQGLYYLHSKGKMHRDIKGANILLTDNGHVKLADFGVSAQITATIAKRKSFIGTPYWMAP
  EVAAVERKGGYNQLCDLWAVGITAIELAELQPPMFDLHPMRALFLMTKSNFQPPKLKDKM
  KWSNSFHHFVKMALTKNPKKRPTAEKLLQHPFVTQHLTRSLAIELLDKVNNPDHSTYHDF
  DDDDPEPLVAVPHRIHSTSRNVREEKTRSEITFGQVKFDPPLRKETEPHHELPDSDGFLD
  SSEEIYYTARSNLDLQLEYGQGHQGGYFLGANKSLLKSVEEELHQRGHVAHLEDDEGDDD
  ESKHSTLKAKIPPPLPPKPKSIFIPQEMHSTEDENQGTIKRCPMSGSPAKPSQVPPRPPP
  PRLPPHKPVALGNGMSSFQLNGERDGSLCQQQNEHRGTNLSRKEKKDVPKPISNGLPPTP
  KVHMGACFSKVFNGCPLKIHCASSWINPDTRDQYLIFGAEEGIYTLNLNELHETSMEQLF
  PRRCTWLYVMNNCLLSISGKASQLYSHNLPGLFDYARQMQKLPVAIPAHKLPDRILPRKF
  SVSAKIPETKWCQKCCVVRNPYTGHKYLCGALQTSIVLLEWVEPMQKFMLIKHIDFPIPC
  PLRMFEMLVVPEQEYPLVCVGVSRGRDFNQVVRFETVNPNSTSSWFTESDTPQTNVTHVT
  QLERDTILVCLDCCIKIVNLQGRLKSSRKLSSELTFDFQIESIVCLQDSVLAFWKHGMQG
  RSFRSNEVTQEISDSTRIFRLLGSDRVVVLESRPTDNPTANSNLYILAGHENSY
• Function: May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway.
• Tissue Specificity: Ubiquitously expressed in all tissues examined, with high levels in heart, brain, placenta, skeletal muscle, kidney and pancreas and lower levels in lung and liver.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

11 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 Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[6]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[7]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[10]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [8] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [9] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [11] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.