Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9C3KFI)

• DOT Name: Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)
• Synonyms: CaM-KK 2; CaM-kinase kinase 2; CaMKK 2; EC 2.7.11.17; Calcium/calmodulin-dependent protein kinase kinase beta; CaM-KK beta; CaM-kinase kinase beta; CaMKK beta
• Gene Name: CAMKK2
• UniProt ID: KKCC2_HUMAN
• PDB ID: 2ZV2; 5UY6; 5UYJ; 5VT1; 5YV8; 5YV9; 5YVA; 5YVB; 5YVC; 6BKU; 6BLE; 6BQL; 6BQP; 6BQQ; 6BRC; 6CMJ; 6EF5; 6EWW; 6FEL; 6Y3O; 6Y4K; 6Y6B; 6Y8A
• EC Number: 2.7.11.17
• Pfam ID: PF00069
• Sequence:
  MSSCVSSQPSSNRAAPQDELGGRGSSSSESQKPCEALRGLSSLSIHLGMESFIVVTECEP
  GCAVDLGLARDRPLEADGQEVPLDTSGSQARPHLSGRKLSLQERSQGGLAAGGSLDMNGR
  CICPSLPYSPVSSPQSSPRLPRRPTVESHHVSITGMQDCVQLNQYTLKDEIGKGSYGVVK
  LAYNENDNTYYAMKVLSKKKLIRQAGFPRRPPPRGTRPAPGGCIQPRGPIEQVYQEIAIL
  KKLDHPNVVKLVEVLDDPNEDHLYMVFELVNQGPVMEVPTLKPLSEDQARFYFQDLIKGI
  EYLHYQKIIHRDIKPSNLLVGEDGHIKIADFGVSNEFKGSDALLSNTVGTPAFMAPESLS
  ETRKIFSGKALDVWAMGVTLYCFVFGQCPFMDERIMCLHSKIKSQALEFPDQPDIAEDLK
  DLITRMLDKNPESRIVVPEIKLHPWVTRHGAEPLPSEDENCTLVEVTEEEVENSVKHIPS
  LATVILVKTMIRKRSFGNPFEGSRREERSLSAPGNLLTKKPTRECESLSELKEARQRRQP
  PGHRPAPRGGGGSALVRGSPCVESCWAPAPGSPARMHPLRPEEAMEPE
• Function: Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin-binding domain are inactive. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals. Seems to be involved in hippocampal activation of CREB1. May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.
• Tissue Specificity: Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Adipocytokine sig.ling pathway (hsa04920)
  Oxytocin sig.ling pathway (hsa04921)
  Alcoholic liver disease (hsa04936)
  Alcoholism (hsa05034)
• Reactome Pathway:
  CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde (R-HSA-442729)
  Activation of RAC1 downstream of NMDARs (R-HSA-9619229)
  Activation of AMPK downstream of NMDARs (R-HSA-9619483)
  CaMK IV-mediated phosphorylation of CREB (R-HSA-111932)

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
PX-866	DMYISJK	Phase 2	Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) affects the response to substance of PX-866.	[16]

14 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 Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[7]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[8]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[9]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[15]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[15]

5 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 Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).	[13]

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] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [9] A regulatory feedback loop between Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and the androgen receptor in prostate cancer progression. J Biol Chem. 2012 Jul 13;287(29):24832-43. doi: 10.1074/jbc.M112.370783. Epub 2012 May 31.
• [10] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [11] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [12] 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.
• [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] Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood. Environ Epigenet. 2020 Dec 23;6(1):dvaa021. doi: 10.1093/eep/dvaa021. eCollection 2020.
• [15] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [16] Akt activation by Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells. J Biol Chem. 2017 Aug 25;292(34):14188-14204. doi: 10.1074/jbc.M117.778464. Epub 2017 Jun 20.