Details of Drug Off-Target (DOT)

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

DOT Name	Serine/threonine-protein kinase pim-1 (PIM1)
Synonyms	EC 2.7.11.1
Gene Name	PIM1
UniProt ID	PIM1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1XQZ ; 1XR1 ; 1XWS ; 1YHS ; 1YI3 ; 1YI4 ; 1YWV ; 1YXS ; 1YXT ; 1YXU ; 1YXV ; 1YXX ; 2BIK ; 2BIL ; 2BZH ; 2BZI ; 2BZJ ; 2BZK ; 2C3I ; 2J2I ; 2O3P ; 2O63 ; 2O64 ; 2O65 ; 2OBJ ; 2OI4 ; 2XIX ; 2XIY ; 2XIZ ; 2XJ0 ; 2XJ1 ; 2XJ2 ; 3A99 ; 3BGP ; 3BGQ ; 3BGZ ; 3BWF ; 3C4E ; 3CXW ; 3CY2 ; 3CY3 ; 3DCV ; 3F2A ; 3JPV ; 3JXW ; 3JY0 ; 3JYA ; 3MA3 ; 3QF9 ; 3R00 ; 3R01 ; 3R02 ; 3R04 ; 3T9I ; 3UIX ; 3UMW ; 3UMX ; 3VBQ ; 3VBT ; 3VBV ; 3VBW ; 3VBX ; 3VBY ; 3VC4 ; 3WE8 ; 4A7C ; 4ALU ; 4ALV ; 4ALW ; 4AS0 ; 4BZN ; 4BZO ; 4DTK ; 4ENX ; 4ENY ; 4GW8 ; 4I41 ; 4IAA ; 4JX3 ; 4JX7 ; 4K0Y ; 4K18 ; 4K1B ; 4LL5 ; 4LM5 ; 4LMU ; 4MBI ; 4MBL ; 4MTA ; 4N6Y ; 4N6Z ; 4N70 ; 4RBL ; 4RC2 ; 4RC3 ; 4RC4 ; 4RPV ; 4TY1 ; 4WRS ; 4WSY ; 4WT6 ; 4XH6 ; 4XHK ; 5C1Q ; 5DGZ ; 5DHJ ; 5DIA ; 5DWR ; 5EOL ; 5IIS ; 5IPJ ; 5KCX ; 5KGD ; 5KGE ; 5KGG ; 5KGI ; 5KGK ; 5KZI ; 5MZL ; 5N4N ; 5N4O ; 5N4R ; 5N4U ; 5N4V ; 5N4X ; 5N4Y ; 5N4Z ; 5N50 ; 5N51 ; 5N52 ; 5N5L ; 5N5M ; 5NDT ; 5O11 ; 5O12 ; 5O13 ; 5TEL ; 5TEX ; 5TOE ; 5TUR ; 5V80 ; 5V82 ; 5VUA ; 5VUB ; 5VUC ; 6AYD ; 6BSK ; 6KZI ; 6L11 ; 6L12 ; 6L13 ; 6L14 ; 6L15 ; 6L16 ; 6L17 ; 6MT0 ; 6NO8 ; 6NO9 ; 6PCW ; 6PDI ; 6PDN ; 6PDO ; 6PDP ; 6QXK ; 6VRU ; 6VRV ; 6YKD ; 7OOV ; 7OOW ; 7OOX ; 7QB2 ; 7QFM ; 7XSV ; 7Z6U ; 7ZUN ; 8AFR
EC Number	2.7.11.1
Pfam ID	PF00069
Sequence	MLLSKINSLAHLRAAPCNDLHATKLAPGKEKEPLESQYQVGPLLGSGGFGSVYSGIRVSD NLPVAIKHVEKDRISDWGELPNGTRVPMEVVLLKKVSSGFSGVIRLLDWFERPDSFVLIL ERPEPVQDLFDFITERGALQEELARSFFWQVLEAVRHCHNCGVLHRDIKDENILIDLNRG ELKLIDFGSGALLKDTVYTDFDGTRVYSPPEWIRYHRYHGRSAAVWSLGILLYDMVCGDI PFEHDEEIIRGQVFFRQRVSSECQHLIRWCLALRPSDRPTFEEIQNHPWMQDVLLPQETA EIHLHSLSPGPSK
Function	Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, another proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promotes cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B, induces 14-3-3 proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis. Acts as a positive regulator of mTORC1 signaling by mediating phosphorylation and inhibition of DEPDC5 component of the GATOR1 complex. Acts as a negative regulator of innate immunity by mediating phosphorylation and inactivation of GBP1 in absence of infection: phosphorylation of GBP1 induces interaction with 14-3-3 protein sigma (SFN) and retention in the cytosol. Also phosphorylates and activates the ATP-binding cassette transporter ABCG2, allowing resistance to drugs through their excretion from cells. Promotes brown adipocyte differentiation.
Tissue Specificity	Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines.
KEGG Pathway	JAK-STAT sig.ling pathway (hsa04630 ) AGE-RAGE sig.ling pathway in diabetic complications (hsa04933 ) Pathways in cancer (hsa05200 ) MicroR.s in cancer (hsa05206 ) Acute myeloid leukemia (hsa05221 )
Reactome Pathway	STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518 ) Signaling by FLT3 fusion proteins (R-HSA-9703465 ) Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibrutinib	DMHZCPO	Approved	Serine/threonine-protein kinase pim-1 (PIM1) decreases the response to substance of Ibrutinib.	[37]
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45 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 Serine/threonine-protein kinase pim-1 (PIM1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[19]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[20]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[21]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[22]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[11]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[3]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[18]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[27]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[15]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[34]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[11]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Serine/threonine-protein kinase pim-1 (PIM1).	[35]
AGELADINE A	DMOJ3CW	Investigative	AGELADINE A decreases the activity of Serine/threonine-protein kinase pim-1 (PIM1).	[36]
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⏷ Show the Full List of 45 Drug(s)

References

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2	Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
3	Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
4	Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
5	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.
6	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
7	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
8	ERE-independent ERalpha target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005 Dec 21;245(1-2):53-9. doi: 10.1016/j.mce.2005.10.003. Epub 2005 Nov 17.
9	Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
10	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.
11	Resveratrol attenuates senescence of adipose-derived mesenchymal stem cells and restores their paracrine effects on promoting insulin secretion of INS-1 cells through Pim-1. Eur Rev Med Pharmacol Sci. 2016;20(6):1203-13.
12	Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
13	Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
14	Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
15	A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
16	Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
17	Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
18	Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
19	A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
20	The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
21	Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
22	Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016 Jun 9;127(23):2890-902. doi: 10.1182/blood-2015-11-683581. Epub 2016 Apr 20.
23	Thalidomide alters c-MYB and PIM-1 signaling in K-562 cells. Pharmacol Res. 2006 Aug;54(2):91-6. doi: 10.1016/j.phrs.2006.02.010. Epub 2006 Mar 8.
24	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
25	Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
26	Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
27	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
28	Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5.
29	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
30	Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther. 2014 May;13(5):1194-205. doi: 10.1158/1535-7163.MCT-13-0341. Epub 2014 Jan 16.
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32	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.
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34	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.
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36	A one-pot synthesis and biological activity of ageladine A and analogues. J Med Chem. 2011 Apr 14;54(7):2492-503. doi: 10.1021/jm200039m. Epub 2011 Mar 17.
37	Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.