Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1KTXH)

• DOT Name: Serine/threonine-protein kinase pim-3 (PIM3)
• Synonyms: EC 2.7.11.1
• Gene Name: PIM3
• UniProt ID: PIM3_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MLLSKFGSLAHLCGPGGVDHLPVKILQPAKADKESFEKAYQVGAVLGSGGFGTVYAGSRI
  ADGLPVAVKHVVKERVTEWGSLGGATVPLEVVLLRKVGAAGGARGVIRLLDWFERPDGFL
  LVLERPEPAQDLFDFITERGALDEPLARRFFAQVLAAVRHCHSCGVVHRDIKDENLLVDL
  RSGELKLIDFGSGALLKDTVYTDFDGTRVYSPPEWIRYHRYHGRSATVWSLGVLLYDMVC
  GDIPFEQDEEILRGRLLFRRRVSPECQQLIRWCLSLRPSERPSLDQIAAHPWMLGADGGV
  PESCDLRLCTLDPDDVASTTSSSESL
• Function: Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. May contribute to tumorigenesis through: the delivery of survival signaling through phosphorylation of BAD which induces release of the anti-apoptotic protein Bcl-X(L), the regulation of cell cycle progression, protein synthesis and by regulation of MYC transcriptional activity. Additionally to this role on tumorigenesis, can also negatively regulate insulin secretion by inhibiting the activation of MAPK1/3 (ERK1/2), through SOCS6. Involved also in the control of energy metabolism and regulation of AMPK activity in modulating MYC and PPARGC1A protein levels and cell growth.
• Tissue Specificity: Detected in various tissues, including the heart, brain, lung, kidney, spleen, placenta, skeletal muscle, and peripheral blood leukocytes. Not found or barely expressed in the normal adult endoderm-derived organs such as colon, thymus, liver, or small intestine. However, expression is augmented in premalignant and malignant lesions of these organs.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein kinase pim-3 (PIM3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serine/threonine-protein kinase pim-3 (PIM3).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Serine/threonine-protein kinase pim-3 (PIM3).	[12]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.