Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFVD6AB)

• DOT Name: Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1)
• Synonyms: CaM-KK 1; CaM-kinase kinase 1; CaMKK 1; EC 2.7.11.17; CaM-kinase IV kinase; Calcium/calmodulin-dependent protein kinase kinase alpha; CaM-KK alpha; CaM-kinase kinase alpha; CaMKK alpha
• Gene Name: CAMKK1
• UniProt ID: KKCC1_HUMAN
• PDB ID: 6CCF; 6CD6
• EC Number: 2.7.11.17
• Pfam ID: PF00069
• Sequence:
  MEGGPAVCCQDPRAELVERVAAIDVTHLEEADGGPEPTRNGVDPPPRARAASVIPGSTSR
  LLPARPSLSARKLSLQERPAGSYLEAQAGPYATGPASHISPRAWRRPTIESHHVAISDAE
  DCVQLNQYKLQSEIGKGAYGVVRLAYNESEDRHYAMKVLSKKKLLKQYGFPRRPPPRGSQ
  AAQGGPAKQLLPLERVYQEIAILKKLDHVNVVKLIEVLDDPAEDNLYLVFDLLRKGPVME
  VPCDKPFSEEQARLYLRDVILGLEYLHCQKIVHRDIKPSNLLLGDDGHVKIADFGVSNQF
  EGNDAQLSSTAGTPAFMAPEAISDSGQSFSGKALDVWATGVTLYCFVYGKCPFIDDFILA
  LHRKIKNEPVVFPEEPEISEELKDLILKMLDKNPETRIGVPDIKLHPWVTKNGEEPLPSE
  EEHCSVVEVTEEEVKNSVRLIPSWTTVILVKSMLRKRSFGNPFEPQARREERSMSAPGNL
  LVKEGFGEGGKSPELPGVQEDEAAS
• Function: Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death.
• KEGG Pathway: 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)
  CaMK IV-mediated phosphorylation of CREB (R-HSA-111932)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1).	[10]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] 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.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.