Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKBAVT3)

• DOT Name: Protein kinase C iota type (PRKCI)
• Synonyms: EC 2.7.11.13; Atypical protein kinase C-lambda/iota; PRKC-lambda/iota; aPKC-lambda/iota; nPKC-iota
• Gene Name: PRKCI
• UniProt ID: KPCI_HUMAN
• PDB ID: 1VD2; 1WMH; 1ZRZ; 3A8W; 3A8X; 3ZH8; 5LI1; 5LI9; 5LIH; 6ILZ
• EC Number: 2.7.11.13
• Pfam ID: PF00130 ; PF00564 ; PF00069 ; PF00433
• Sequence:
  MPTQRDSSTMSHTVAGGGSGDHSHQVRVKAYYRGDIMITHFEPSISFEGLCNEVRDMCSF
  DNEQLFTMKWIDEEGDPCTVSSQLELEEAFRLYELNKDSELLIHVFPCVPERPGMPCPGE
  DKSIYRRGARRWRKLYCANGHTFQAKRFNRRAHCAICTDRIWGLGRQGYKCINCKLLVHK
  KCHKLVTIECGRHSLPQEPVMPMDQSSMHSDHAQTVIPYNPSSHESLDQVGEEKEAMNTR
  ESGKASSSLGLQDFDLLRVIGRGSYAKVLLVRLKKTDRIYAMKVVKKELVNDDEDIDWVQ
  TEKHVFEQASNHPFLVGLHSCFQTESRLFFVIEYVNGGDLMFHMQRQRKLPEEHARFYSA
  EISLALNYLHERGIIYRDLKLDNVLLDSEGHIKLTDYGMCKEGLRPGDTTSTFCGTPNYI
  APEILRGEDYGFSVDWWALGVLMFEMMAGRSPFDIVGSSDNPDQNTEDYLFQVILEKQIR
  IPRSLSVKAASVLKSFLNKDPKERLGCHPQTGFADIQGHPFFRNVDWDMMEQKQVVPPFK
  PNISGEFGLDNFDSQFTNEPVQLTPDDDDIVRKIDQSEFEGFEYINPLLMSAEECV
• Function: Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. Involved in early synaptic long term potentiation phase in CA1 hippocampal cells and short term memory formation.
• Tissue Specificity: Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Endocytosis (hsa04144)
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Platelet activation (hsa04611)
  Insulin sig.ling pathway (hsa04910)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  p75NTR recruits signalling complexes (R-HSA-209543)
  Tight junction interactions (R-HSA-420029)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Protein kinase C iota type (PRKCI) affects the response to substance of Acetaminophen.	[17]
Doxorubicin	DMVP5YE	Approved	Protein kinase C iota type (PRKCI) affects the response to substance of Doxorubicin.	[18]
Cisplatin	DMRHGI9	Approved	Protein kinase C iota type (PRKCI) affects the response to substance of Cisplatin.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein kinase C iota type (PRKCI).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein kinase C iota type (PRKCI).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C iota type (PRKCI).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein kinase C iota type (PRKCI).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein kinase C iota type (PRKCI).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein kinase C iota type (PRKCI).	[6]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Protein kinase C iota type (PRKCI).	[5]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Protein kinase C iota type (PRKCI).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Protein kinase C iota type (PRKCI).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Protein kinase C iota type (PRKCI).	[10]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Protein kinase C iota type (PRKCI).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein kinase C iota type (PRKCI).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein kinase C iota type (PRKCI).	[15]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Protein kinase C iota type (PRKCI).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Irinotecan increases the phosphorylation of Protein kinase C iota type (PRKCI).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein kinase C iota type (PRKCI).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein kinase C iota type (PRKCI).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein kinase C iota type (PRKCI).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the localization of Protein kinase C iota type (PRKCI).	[12]

References

• [1] 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.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [4] 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.
• [5] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [6] 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.
• [7] Gefitinib ("Iressa", ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother Pharmacol. 2005 Apr;55(4):393-403. doi: 10.1007/s00280-004-0904-0. Epub 2004 Oct 5.
• [8] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [9] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [10] 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.
• [11] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [12] Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Toxicology. 2011 Apr 11;282(3):122-8. doi: 10.1016/j.tox.2011.01.018. Epub 2011 Feb 2.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [17] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.