Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9OXGS9)

• DOT Name: Myocardin-related transcription factor B (MRTFB)
• Synonyms: MRTF-B; MKL/myocardin-like protein 2; Megakaryoblastic leukemia 2
• Gene Name: MRTFB
• Related Disease:
  Acute megakaryoblastic leukemia
  Autism
  Lung adenocarcinoma
  Malignant soft tissue neoplasm
  Pervasive developmental disorder
  Sarcoma
  Schizophrenia
  Vascular disease
  Autism spectrum disorder
  Glaucoma/ocular hypertension
• UniProt ID: MRTFB_HUMAN
• Pfam ID: PF02755 ; PF02037
• Sequence:
  MIDSSKKQQQGFPEILTAGDFEPLKEKECLEGSNQKSLKEVLQLRLQQRRTREQLVDQGI
  MPPLKSPAAFHEQIKSLERARTENFLKHKIRSRPDRSELVRMHILEETFAEPSLQATQMK
  LKRARLADDLNEKIAQRPGPMELVEKNILPVDSSVKEAIIGVGKEDYPHTQGDFSFDEDS
  SDALSPDQPASQESQGSAASPSEPKVSESPSPVTTNTPAQFASVSPTVPEFLKTPPTADQ
  PPPRPAAPVLPTNTVSSAKPGPALVKQSHPKNPNDKHRSKKCKDPKPRVKKLKYHQYIPP
  DQKGEKNEPQMDSNYARLLQQQQLFLQLQILSQQKQHYNYQTILPAPFKPLNDKNSNSGN
  SALNNATPNTPRQNTSTPVRKPGPLPSSLDDLKVSELKTELKLRGLPVSGTKPDLIERLK
  PYQEVNSSGLAAGGIVAVSSSAIVTSNPEVTVALPVTTLHNTVTSSVSTLKAELPPTGTS
  NATRVENVHSPLPISPSPSEQSSLSTDDTNMADTFTEIMTMMSPSQFLSSSPLRMTNNED
  SLSPTSSTLSNLELDAAEKDRKLQEKEKQIEELKRKLEQEQKLVEVLKMQLEVEKRGQQQ
  RPLEAQPSAPGHSVKSDQKHGSLGSSIKDEASLPDCSSSRQPIPVASHAVGQPVSTGGQT
  LVAKKAVVIKQEVPVGQAEQQSVVSQFYVSSQGQPPPAVVAQPQALLTTQTAQLLLPVSI
  QGSSVTSVQLPVGSLKLQTSPQAGMQTQPQIATAAQIPTAALASGLAPTVPQTQDTFPQH
  VLSQPQQVRKVFTNSASSNTVLPYQRHPAPAVQQPFINKASNSVLQSRNAPLPSLQNGPN
  TPNKPSSPPPPQQFVVQHSLFGSPVAKTKDPPRYEEAIKQTRSTQAPLPEISNAHSQQMD
  DLFDILIKSGEISLPIKEEPSPISKMRPVTASITTMPVNTVVSRPPPQVQMAPPVSLEPM
  GSLSASLENQLEAFLDGTLPSANEIPPLQSSSEDREPFSLIEDLQNDLLSHSGMLDHSHS
  PMETSETQFAAGTPCLSLDLSDSNLDNMEWLDITMPNSSSGLTPLSTTAPSMFSADFLDP
  QDLPLPWD
• Function: Acts as a transcriptional coactivator of serum response factor (SRF). Required for skeletal myogenic differentiation.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[4]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[5]
Sarcoma	DISZDG3U	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Vascular disease	DISVS67S	Strong	Biomarker	[6]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[5]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[7]

5 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 Myocardin-related transcription factor B (MRTFB).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Myocardin-related transcription factor B (MRTFB).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Myocardin-related transcription factor B (MRTFB).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Myocardin-related transcription factor B (MRTFB).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Myocardin-related transcription factor B (MRTFB).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myocardin-related transcription factor B (MRTFB).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myocardin-related transcription factor B (MRTFB).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Myocardin-related transcription factor B (MRTFB).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Myocardin-related transcription factor B (MRTFB).	[14]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Myocardin-related transcription factor B (MRTFB).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Myocardin-related transcription factor B (MRTFB).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Myocardin-related transcription factor B (MRTFB).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Myocardin-related transcription factor B (MRTFB).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Myocardin-related transcription factor B (MRTFB).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myocardin-related transcription factor B (MRTFB).	[20]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Myocardin-related transcription factor B (MRTFB).	[21]

References

• [1] Divergent Regulation of Actin Dynamics and Megakaryoblastic Leukemia-1 and -2 (Mkl1/2) by cAMP in Endothelial and Smooth Muscle Cells.Sci Rep. 2017 Jun 16;7(1):3681. doi: 10.1038/s41598-017-03337-0.
• [2] Linkage and candidate gene studies of autism spectrum disorders in European populations.Eur J Hum Genet. 2010 Sep;18(9):1013-9. doi: 10.1038/ejhg.2010.69. Epub 2010 May 5.
• [3] Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells.Cancer Sci. 2017 Jul;108(7):1394-1404. doi: 10.1111/cas.13271. Epub 2017 Jun 10.
• [4] RREB1-MKL2 fusion in biphenotypic "oropharyngeal" sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?.Genes Chromosomes Cancer. 2018 Apr;57(4):203-210. doi: 10.1002/gcc.22521. Epub 2018 Jan 25.
• [5] Synaptic localisation of SRF coactivators, MKL1 and MKL2, and their role in dendritic spine morphology.Sci Rep. 2018 Jan 15;8(1):727. doi: 10.1038/s41598-017-18905-7.
• [6] Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors.J Biol Chem. 2007 Dec 21;282(51):37244-55. doi: 10.1074/jbc.M708137200. Epub 2007 Oct 17.
• [7] Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery.Mol Ther. 2018 Dec 5;26(12):2812-2822. doi: 10.1016/j.ymthe.2018.09.004. Epub 2018 Sep 11.
• [8] 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.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] 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.
• [21] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.