Details of Drug Off-Target (DOT)

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

• DOT Name: Myosin regulatory light chain 12B (MYL12B)
• Synonyms: MLC-2A; MLC-2; Myosin regulatory light chain 2-B, smooth muscle isoform; Myosin regulatory light chain 20 kDa; MLC20; Myosin regulatory light chain MRLC2; SHUJUN-1
• Gene Name: MYL12B
• Related Disease:
  Bone osteosarcoma
  Cardiomyopathy
  Depression
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  Familial hypertrophic cardiomyopathy
  Hepatocellular carcinoma
  Hypercholesterolemia, familial, 1
  Hypertrophic cardiomyopathy
  Lung cancer
  Lung carcinoma
  Malignant soft tissue neoplasm
  Myopathy
  Osteosarcoma
  Sarcoma
  Schizophrenia
  Clear cell renal carcinoma
  Neoplasm
• UniProt ID: ML12B_HUMAN
• Pfam ID: PF08976 ; PF13499
• Sequence:
  MSSKKAKTKTTKKRPQRATSNVFAMFDQSQIQEFKEAFNMIDQNRDGFIDKEDLHDMLAS
  LGKNPTDAYLDAMMNEAPGPINFTMFLTMFGEKLNGTDPEDVIRNAFACFDEEATGTIQE
  DYLRELLTTMGDRFTDEEVDELYREAPIDKKGNFNYIEFTRILKHGAKDKDD
• Function: Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Phosphorylation triggers actin polymerization in vascular smooth muscle. Implicated in cytokinesis, receptor capping, and cell locomotion.
• Tissue Specificity: Ubiquitously expressed in various hematopoietic cells.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Motor proteins (hsa04814)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  Smooth Muscle Contraction (R-HSA-445355)
  RHO GTPases activate PKNs (R-HSA-5625740)
  RHO GTPases activate CIT (R-HSA-5625900)
  RHO GTPases Activate ROCKs (R-HSA-5627117)
  RHO GTPases activate PAKs (R-HSA-5627123)
  EPHA-mediated growth cone collapse (R-HSA-3928663)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[1]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[4]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[4]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[1]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[1]
Sarcoma	DISZDG3U	Strong	Altered Expression	[1]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[9]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Myosin regulatory light chain 12B (MYL12B).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Myosin regulatory light chain 12B (MYL12B).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Myosin regulatory light chain 12B (MYL12B).	[30]

21 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 Myosin regulatory light chain 12B (MYL12B).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myosin regulatory light chain 12B (MYL12B).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Myosin regulatory light chain 12B (MYL12B).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myosin regulatory light chain 12B (MYL12B).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Myosin regulatory light chain 12B (MYL12B).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of Myosin regulatory light chain 12B (MYL12B).	[21]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Myosin regulatory light chain 12B (MYL12B).	[22]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Myosin regulatory light chain 12B (MYL12B).	[23]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Myosin regulatory light chain 12B (MYL12B).	[25]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Myosin regulatory light chain 12B (MYL12B).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Myosin regulatory light chain 12B (MYL12B).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Myosin regulatory light chain 12B (MYL12B).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Myosin regulatory light chain 12B (MYL12B).	[32]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Myosin regulatory light chain 12B (MYL12B).	[33]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Myosin regulatory light chain 12B (MYL12B).	[34]

References

• [1] Human smooth muscle myosin light chain-2 gene expression is repressed in ras transformed fibroblast cells.Cell Growth Differ. 1992 Jan;3(1):1-10.
• [2] In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain.Arch Biochem Biophys. 2014 Jun 15;552-553:29-39. doi: 10.1016/j.abb.2013.12.011. Epub 2013 Dec 26.
• [3] The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.Neuropsychopharmacology. 2017 Oct;42(11):2105-2113. doi: 10.1038/npp.2017.84. Epub 2017 Apr 26.
• [4] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy.ESC Heart Fail. 2019 Apr;6(2):406-415. doi: 10.1002/ehf2.12410. Epub 2019 Jan 28.
• [5] Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM.J Mol Med (Berl). 2019 Jul;97(7):1033-1047. doi: 10.1007/s00109-019-01791-z. Epub 2019 May 17.
• [6] Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells.J Biol Chem. 1998 Feb 27;273(9):5146-54. doi: 10.1074/jbc.273.9.5146.
• [7] Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.FASEB J. 2019 Mar;33(3):3152-3166. doi: 10.1096/fj.201801402R. Epub 2018 Oct 26.
• [8] Aberrant upregulation of a novel integrin alpha subunit gene at 3p21.3 in small cell lung cancer.Oncogene. 1994 Feb;9(2):611-9.
• [9] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [10] Morphine enhances renal cell carcinoma aggressiveness through promotes survivin level.Ren Fail. 2017 Nov;39(1):258-264. doi: 10.1080/0886022X.2016.1256322. Epub 2016 Nov 21.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [20] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [21] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [22] 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.
• [23] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [24] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [25] 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.
• [26] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [27] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [28] 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.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [31] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [32] 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.
• [33] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [34] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.