Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4ZYV73)

• DOT Name: Pleckstrin homology domain-containing family M member 2 (PLEKHM2)
• Synonyms: PH domain-containing family M member 2; Salmonella-induced filaments A and kinesin-interacting protein; SifA and kinesin-interacting protein
• Gene Name: PLEKHM2
• Related Disease:
  Adult glioblastoma
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Bladder cancer
  Dilated cardiomyopathy 1A
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Insomnia
  Left ventricular noncompaction
  Neoplasm
  Skin cancer
  Skin carcinoma
  Tauopathy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Cutaneous melanoma
  Melanoma
  Breast carcinoma
  Dilated cardiomyopathy
  Small-cell lung cancer
• UniProt ID: PKHM2_HUMAN
• PDB ID: 3CXB; 3HW2; 3ZFW
• Pfam ID: PF00169 ; PF02759
• Sequence:
  MEPGEVKDRILENISLSVKKLQSYFAACEDEIPAIRNHDKVLQRLCEHLDHALLYGLQDL
  SSGYWVLVVHFTRREAIKQIEVLQHVATNLGRSRAWLYLALNENSLESYLRLFQENLGLL
  HKYYVKNALVCSHDHLTLFLTLVSGLEFIRFELDLDAPYLDLAPYMPDYYKPQYLLDFED
  RLPSSVHGSDSLSLNSFNSVTSTNLEWDDSAIAPSSEDYDFGDVFPAVPSVPSTDWEDGD
  LTDTVSGPRSTASDLTSSKASTRSPTQRQNPFNEEPAETVSSSDTTPVHTTSQEKEEAQA
  LDPPDACTELEVIRVTKKKKIGKKKKSRSDEEASPLHPACSQKKCAKQGDGDSRNGSPSL
  GRDSPDTMLASPQEEGEGPSSTTESSERSEPGLLIPEMKDTSMERLGQPLSKVIDQLNGQ
  LDPSTWCSRAEPPDQSFRTGSPGDAPERPPLCDFSEGLSAPMDFYRFTVESPSTVTSGGG
  HHDPAGLGQPLHVPSSPEAAGQEEEGGGGEGQTPRPLEDTTREAQELEAQLSLVREGPVS
  EPEPGTQEVLCQLKRDQPSPCLSSAEDSGVDEGQGSPSEMVHSSEFRVDNNHLLLLMIHV
  FRENEEQLFKMIRMSTGHMEGNLQLLYVLLTDCYVYLLRKGATEKPYLVEEAVSYNELDY
  VSVGLDQQTVKLVCTNRRKQFLLDTADVALAEFFLASLKSAMIKGCREPPYPSILTDATM
  EKLALAKFVAQESKCEASAVTVRFYGLVHWEDPTDESLGPTPCHCSPPEGTITKEGMLHY
  KAGTSYLGKEHWKTCFVVLSNGILYQYPDRTDVIPLLSVNMGGEQCGGCRRANTTDRPHA
  FQVILSDRPCLELSAESEAEMAEWMQHLCQAVSKGVIPQGVAPSPCIPCCLVLTDDRLFT
  CHEDCQTSFFRSLGTAKLGDISAVSTEPGKEYCVLEFSQDSQQLLPPWVIYLSCTSELDR
  LLSALNSGWKTIYQVDLPHTAIQEASNKKKFEDALSLIHSAWQRSDSLCRGRASRDPWC
• Function: Plays a role in lysosomes movement and localization at the cell periphery acting as an effector of ARL8B. Required for ARL8B to exert its effects on lysosome location, recruits kinesin-1 to lysosomes and hence direct their movement toward microtubule plus ends. Binding to ARL8B provides a link from lysosomal membranes to plus-end-directed motility. Critical factor involved in NK cell-mediated cytotoxicity. Drives the polarization of cytolytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells. Required for maintenance of the Golgi apparatus organization. May play a role in membrane tubulation.
• KEGG Pathway: Salmonella infection (hsa05132)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Insomnia	DIS0AFR7	Strong	Biomarker	[7]
Left ventricular noncompaction	DISJ4QEG	Strong	SusceptibilityMutation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Skin cancer	DISTM18U	Strong	Biomarker	[9]
Skin carcinoma	DISUZREN	Strong	Genetic Variation	[10]
Tauopathy	DISY2IPA	Strong	Altered Expression	[3]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[11]
Melanoma	DIS1RRCY	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal recessive	[13]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[8]

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 Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pleckstrin homology domain-containing family M member 2 (PLEKHM2).	[23]

References

• [1] Lipid phosphatases SKIP and SHIP2 regulate fibronectin-dependent cell migration in glioblastoma.FEBS J. 2019 Mar;286(6):1120-1135. doi: 10.1111/febs.14769. Epub 2019 Feb 16.
• [2] A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.PLoS Genet. 2008 Jul 18;4(7):e1000129. doi: 10.1371/journal.pgen.1000129.
• [3] A Novel Microtubule-Tau Association Enhancer and Neuroprotective Drug Candidate: Ac-SKIP.Front Cell Neurosci. 2019 Oct 1;13:435. doi: 10.3389/fncel.2019.00435. eCollection 2019.
• [4] SKIP expression is correlated with clinical prognosis in patients with bladder cancer.Int J Clin Exp Pathol. 2014 Mar 15;7(4):1695-701. eCollection 2014.
• [5] PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction.Hum Mol Genet. 2015 Dec 20;24(25):7227-40. doi: 10.1093/hmg/ddv423. Epub 2015 Oct 12.
• [6] High SKIP expression is correlated with poor prognosis and cell proliferation of hepatocellular carcinoma.Med Oncol. 2013;30(3):537. doi: 10.1007/s12032-013-0537-4. Epub 2013 May 22.
• [7] Integrative analysis of genome-wide association study and brain region related enhancer maps identifies biological pathways for insomnia.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:180-185. doi: 10.1016/j.pnpbp.2018.05.026. Epub 2018 Jun 6.
• [8] PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable response to ALK inhibitors.Lung Cancer. 2020 Jan;139:146-150. doi: 10.1016/j.lungcan.2019.11.002. Epub 2019 Nov 6.
• [9] Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.BMC Med Res Methodol. 2012 Aug 3;12:116. doi: 10.1186/1471-2288-12-116.
• [10] MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.Br J Cancer. 2015 Jul 14;113(2):354-63. doi: 10.1038/bjc.2015.231. Epub 2015 Jun 23.
• [11] MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.Int J Cancer. 2015 Feb 1;136(3):618-31. doi: 10.1002/ijc.29018. Epub 2014 Jun 18.
• [12] Expression and prognostic role of SKIP in human breast carcinoma.J Mol Histol. 2014 Apr;45(2):169-80. doi: 10.1007/s10735-013-9546-z. Epub 2013 Oct 23.
• [13] 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.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.
• [23] 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.