Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEU2G41)

• DOT Name: Serine/threonine-protein kinase MAK (MAK)
• Synonyms: EC 2.7.11.1; Male germ cell-associated kinase
• Gene Name: MAK
• Related Disease:
  Central nervous system neoplasm
  Inherited retinal dystrophy
  Retinitis pigmentosa 62
  Ciliopathy
  Disorder of orbital region
  Neoplasm
  Prostate neoplasm
  Retinopathy
  Retinitis pigmentosa
  Vitelliform macular dystrophy
• UniProt ID: MAK_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MNRYTTMRQLGDGTYGSVLMGKSNESGELVAIKRMKRKFYSWDECMNLREVKSLKKLNHA
  NVIKLKEVIRENDHLYFIFEYMKENLYQLMKDRNKLFPESVIRNIMYQILQGLAFIHKHG
  FFHRDMKPENLLCMGPELVKIADFGLARELRSQPPYTDYVSTRWYRAPEVLLRSSVYSSP
  IDVWAVGSIMAELYMLRPLFPGTSEVDEIFKICQVLGTPKKSDWPEGYQLASSMNFRFPQ
  CVPINLKTLIPNASNEAIQLMTEMLNWDPKKRPTASQALKHPYFQVGQVLGPSSNHLESK
  QSLNKQLQPLESKPSLVEVEPKPLPDIIDQVVGQPQPKTSQQPLQPIQPPQNLSVQQPPK
  QQSQEKPPQTLFPSIVKNMPTKPNGTLSHKSGRRRWGQTIFKSGDSWEELEDYDFGASHS
  KKPSMGVFKEKRKKDSPFRLPEPVPSGSNHSTGENKSLPAVTSLKSDSELSTAPTSKQYY
  LKQSRYLPGVNPKKVSLIASGKEINPHTWSNQLFPKSLGPVGAELAFKRSNAGNLGSYAT
  YNQSGYIPSFLKKEVQSAGQRIHLAPLNATASEYTWNTKTGRGQFSGRTYNPTAKNLNIV
  NRAQPIPSVHGRTDWVAKYGGHR
• Function: Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors. Phosphorylates FZR1 in a cell cycle-dependent manner. Plays a role in the transcriptional coactivation of AR. Could play an important function in spermatogenesis. May play a role in chromosomal stability in prostate cancer cells.
• Tissue Specificity: Expressed in prostate cancer cell lines at generally higher levels than in normal prostate epithelial cell lines. Isoform 1 is expressed in kidney, testis, lung, trachea, and retina. Isoform 2 is retina-specific where it is expressed in rod and cone photoreceptors.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central nervous system neoplasm	DISFC18W	Definitive	Biomarker	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal recessive	[2]
Retinitis pigmentosa 62	DIS1KF7Q	Definitive	Autosomal recessive	[3]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[8]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[9]
Vitelliform macular dystrophy	DISEFYYN	Limited	Biomarker	[10]

16 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 Serine/threonine-protein kinase MAK (MAK).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase MAK (MAK).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine/threonine-protein kinase MAK (MAK).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/threonine-protein kinase MAK (MAK).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Serine/threonine-protein kinase MAK (MAK).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Serine/threonine-protein kinase MAK (MAK).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Serine/threonine-protein kinase MAK (MAK).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Serine/threonine-protein kinase MAK (MAK).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase MAK (MAK).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Serine/threonine-protein kinase MAK (MAK).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Serine/threonine-protein kinase MAK (MAK).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Serine/threonine-protein kinase MAK (MAK).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein kinase MAK (MAK).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine/threonine-protein kinase MAK (MAK).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Serine/threonine-protein kinase MAK (MAK).	[24]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Serine/threonine-protein kinase MAK (MAK).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase MAK (MAK).	[21]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Slowly progressive retinitis pigmentosa caused by two novel mutations in the MAK gene.Ophthalmic Genet. 2018 Aug;39(4):508-511. doi: 10.1080/13816810.2018.1474369. Epub 2018 May 21.
• [5] Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22671-6. doi: 10.1073/pnas.1009437108. Epub 2010 Dec 8.
• [6] Classification or non-classification of substances with positive tumor findings in animal studies: Guidance by the German MAK commission.Regul Toxicol Pharmacol. 2019 Nov;108:104444. doi: 10.1016/j.yrtph.2019.104444. Epub 2019 Aug 18.
• [7] Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells.Cancer Res. 2006 Sep 1;66(17):8439-47. doi: 10.1158/0008-5472.CAN-06-1636.
• [8] Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.Invest Ophthalmol Vis Sci. 2011 Dec 28;52(13):9665-73. doi: 10.1167/iovs.11-8527.
• [9] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq.Exp Eye Res. 2014 Dec;129:93-106. doi: 10.1016/j.exer.2014.11.001. Epub 2014 Nov 5.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1. Bioorg Med Chem. 2011 Jun 15;19(12):3717-31. doi: 10.1016/j.bmc.2011.02.032. Epub 2011 Feb 27.