Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9OVWCV)

• DOT Name: Formin-like protein 2 (FMNL2)
• Synonyms: Formin homology 2 domain-containing protein 2
• Gene Name: FMNL2
• Related Disease:
  Glaucoma/ocular hypertension
  Melanoma
  Advanced cancer
  Colorectal carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Open-angle glaucoma
  Stroke
  Acute myelogenous leukaemia
  Lung cancer
  Lung carcinoma
• UniProt ID: FMNL2_HUMAN
• PDB ID: 4YC7
• Pfam ID: PF06367 ; PF06371 ; PF02181
• Sequence:
  MGNAGSMDSQQTDFRAHNVPLKLPMPEPGELEERFAIVLNAMNLPPDKARLLRQYDNEKK
  WELICDQERFQVKNPPHTYIQKLKGYLDPAVTRKKFRRRVQESTQVLRELEISLRTNHIG
  WVREFLNEENKGLDVLVEYLSFAQYAVTFDFESVESTVESSVDKSKPWSRSIEDLHRGSN
  LPSPVGNSVSRSGRHSALRYNTLPSRRTLKNSRLVSKKDDVHVCIMCLRAIMNYQYGFNM
  VMSHPHAVNEIALSLNNKNPRTKALVLELLAAVCLVRGGHEIILSAFDNFKEVCGEKQRF
  EKLMEHFRNEDNNIDFMVASMQFINIVVHSVEDMNFRVHLQYEFTKLGLDEYLDKLKHTE
  SDKLQVQIQAYLDNVFDVGALLEDAETKNAALERVEELEENISHLSEKLQDTENEAMSKI
  VELEKQLMQRNKELDVVREIYKDANTQVHTLRKMVKEKEEAIQRQSTLEKKIHELEKQGT
  IKIQKKGDGDIAILPVVASGTLSMGSEVVAGNSVGPTMGAASSGPLPPPPPPLPPSSDTP
  ETVQNGPVTPPMPPPPPPPPPPPPPPPPPPPPPLPGPAAETVPAPPLAPPLPSAPPLPGT
  SSPTVVFNSGLAAVKIKKPIKTKFRMPVFNWVALKPNQINGTVFNEIDDERILEDLNVDE
  FEEIFKTKAQGPAIDLSSSKQKIPQKGSNKVTLLEANRAKNLAITLRKAGKTADEICKAI
  HVFDLKTLPVDFVECLMRFLPTENEVKVLRLYERERKPLENLSDEDRFMMQFSKIERLMQ
  KMTIMAFIGNFAESIQMLTPQLHAIIAASVSIKSSQKLKKILEIILALGNYMNSSKRGAV
  YGFKLQSLDLLLDTKSTDRKQTLLHYISNVVKEKYHQVSLFYNELHYVEKAAAVSLENVL
  LDVKELQRGMDLTKREYTMHDHNTLLKEFILNNEGKLKKLQDDAKIAQDAFDDVVKYFGE
  NPKTTPPSVFFPVFVRFVKAYKQAEEENELRKKQEQALMEKLLEQEALMEQQDPKSPSHK
  SKRQQQELIAELRRRQVKDNRHVYEGKDGAIEDIITVLKTVPFTARTAKRGSRFFCEPVL
  TEEYHY
• Function: Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[1]
Stroke	DISX6UHX	moderate	Genetic Variation	[8]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Lung cancer	DISCM4YA	Limited	Altered Expression	[10]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[10]

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 Formin-like protein 2 (FMNL2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Formin-like protein 2 (FMNL2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Formin-like protein 2 (FMNL2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Formin-like protein 2 (FMNL2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Formin-like protein 2 (FMNL2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Formin-like protein 2 (FMNL2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Formin-like protein 2 (FMNL2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Formin-like protein 2 (FMNL2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Formin-like protein 2 (FMNL2).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Formin-like protein 2 (FMNL2).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Formin-like protein 2 (FMNL2).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Formin-like protein 2 (FMNL2).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Formin-like protein 2 (FMNL2).	[21]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Formin-like protein 2 (FMNL2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Formin-like protein 2 (FMNL2).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Formin-like protein 2 (FMNL2).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Formin-like protein 2 (FMNL2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Formin-like protein 2 (FMNL2).	[28]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Formin-like protein 2 (FMNL2).	[21]

References

• [1] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [2] MicroRNA-22 targets FMNL2 to inhibit melanoma progression via the regulation of the Wnt/-catenin signaling pathway and epithelial-mesenchymal transition.Eur Rev Med Pharmacol Sci. 2019 Jun;23(12):5332-5342. doi: 10.26355/eurrev_201906_18200.
• [3] Formin-like2 regulates Rho/ROCK pathway to promote actin assembly and cell invasion of colorectal cancer.Cancer Sci. 2015 Oct;106(10):1385-93. doi: 10.1111/cas.12768.
• [4] A novel long noncoding RNA, LINC00483 promotes proliferation and metastasis via modulating of FMNL2 in CRC.Biochem Biophys Res Commun. 2019 Feb 5;509(2):441-447. doi: 10.1016/j.bbrc.2018.12.090. Epub 2018 Dec 26.
• [5] Down-regulation of formin-like 2 predicts poor prognosis in hepatocellular carcinoma.Hum Pathol. 2011 Nov;42(11):1603-12. doi: 10.1016/j.humpath.2010.08.025. Epub 2011 Apr 14.
• [6] Overexpression of FMNL2 is closely related to metastasis of colorectal cancer.Int J Colorectal Dis. 2008 Nov;23(11):1041-7. doi: 10.1007/s00384-008-0520-2. Epub 2008 Jul 30.
• [7] BRAF immunohistochemistry predicts sentinel lymph node involvement in intermediate thickness melanomas.PLoS One. 2019 Apr 30;14(4):e0216043. doi: 10.1371/journal.pone.0216043. eCollection 2019.
• [8] Genome-wide association analysis of ischemic stroke in young adults.G3 (Bethesda). 2011 Nov;1(6):505-14. doi: 10.1534/g3.111.001164. Epub 2011 Nov 1.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] LncRNA-RMRP Acts as an Oncogene in Lung Cancer.PLoS One. 2016 Dec 1;11(12):e0164845. doi: 10.1371/journal.pone.0164845. eCollection 2016.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] 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.
• [20] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.