Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8M5GVO)

• DOT Name: cAMP-dependent protein kinase inhibitor alpha (PKIA)
• Synonyms: PKI-alpha; cAMP-dependent protein kinase inhibitor, muscle/brain isoform
• Gene Name: PKIA
• UniProt ID: IPKA_HUMAN
• PDB ID: 1CMK ; 1JLU ; 1Q8T ; 1VEB ; 1XH4 ; 1XH5 ; 1XH6 ; 1XH7 ; 1XH8 ; 1XH9 ; 1XHA ; 1YDR ; 2C1A ; 2C1B ; 2F7E ; 2GNI ; 2JDS ; 2JDT ; 2JDV ; 2L1L ; 2UVX ; 2UVY ; 2UVZ ; 2UW0 ; 2UW3 ; 2UW4 ; 2UW5 ; 2UW6 ; 2UW7 ; 2UW8 ; 2VNW ; 2VNY ; 2VO0 ; 2VO3 ; 2VO6 ; 2VO7 ; 3AMA ; 3AMB ; 3L9L ; 3L9M ; 3L9N ; 3MVJ ; 3NX8 ; 3OOG ; 3OVV ; 3OWP ; 3OXT ; 3P0M ; 3POO ; 3VQH ; 3WYG ; 3X2U ; 3X2V ; 3X2W ; 4AXA ; 4IAC ; 4IAD ; 4IAF ; 4IAI ; 4IAK ; 4IAY ; 4IAZ ; 4IB0 ; 4IB1 ; 4IB3 ; 4IE9 ; 4IJ9 ; 4O21 ; 4O22 ; 4UJ1 ; 4UJ2 ; 4UJ9 ; 4UJA ; 4UJB ; 4WB5 ; 4WB6 ; 4WB7 ; 4WB8 ; 4Z83 ; 4Z84 ; 5BX6 ; 5BX7 ; 5DH9 ; 5LCP ; 5LCQ ; 5LCR ; 5LCT ; 5LCU ; 5M0B ; 5M0C ; 5M0L ; 5M0U ; 5M6V ; 5M6Y ; 5M71 ; 5M75 ; 5N23 ; 5XOJ ; 6E21 ; 6E99 ; 6E9L ; 6FRX ; 6QJ7 ; 6X2U ; 6X2V ; 6X2W ; 7UJX ; 7V0G ; 8FE2 ; 8FE5 ; 8FEC
• Pfam ID: PF02827
• Sequence:
  MTDVETTYADFIASGRTGRRNAIHDILVSSASGNSNELALKLAGLDINKTEGEEDAQRSS
  TEQSGEAQGEAAKSES
• Function: Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains.
• KEGG Pathway: Alcoholism (hsa05034)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	cAMP-dependent protein kinase inhibitor alpha (PKIA) affects the response to substance of Mitomycin.	[19]

15 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 cAMP-dependent protein kinase inhibitor alpha (PKIA).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[14]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of cAMP-dependent protein kinase inhibitor alpha (PKIA).	[17]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [15] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [16] 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.
• [17] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [18] 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.
• [19] 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.