Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRP8R4W)

• DOT Name: Formin-like protein 3 (FMNL3)
• Synonyms: Formin homology 2 domain-containing protein 3; WW domain-binding protein 3; WBP-3
• Gene Name: FMNL3
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Colorectal carcinoma
  Nasopharyngeal carcinoma
  Neoplasm
• UniProt ID: FMNL3_HUMAN
• Pfam ID: PF06367 ; PF06371 ; PF02181
• Sequence:
  MGNLESAEGVPGEPPSVPLLLPPGKMPMPEPCELEERFALVLSSMNLPPDKARLLRQYDN
  EKKWDLICDQERFQVKNPPHTYIQKLQSFLDPSVTRKKFRRRVQESTKVLRELEISLRTN
  HIGWVREFLNDENKGLDVLVDYLSFAQCSVMFDFEGLESGDDGAFDKLRSWSRSIEDLQP
  PSALSAPFTNSLARSARQSVLRYSTLPGRRALKNSRLVSQKDDVHVCILCLRAIMNYQYG
  FNLVMSHPHAVNEIALSLNNKNPRTKALVLELLAAVCLVRGGHEIILAAFDNFKEVCKEL
  HRFEKLMEYFRNEDSNIDFMVACMQFINIVVHSVEDMNFRVHLQYEFTKLGLEEFLQKSR
  HTESEKLQVQIQAYLDNVFDVGGLLEDAETKNVALEKVEELEEHVSHLTEKLLDLENENM
  MRVAELEKQLLQREKELESIKETYENTSHQVHTLRRLIKEKEEAFQRRCHLEPNVRGLES
  VDSEALARVGPAELSEGMPPSDLDLLAPAPPPEEVLPLPPPPAPPLPPPPPPLPDKCPPA
  PPLPGAAPSVVLTVGLSAIRIKKPIKTKFRLPVFNWTALKPNQISGTVFSELDDEKILED
  LDLDKFEELFKTKAQGPALDLICSKNKTAQKAASKVTLLEANRAKNLAITLRKAGRSAEE
  ICRAIHTFDLQTLPVDFVECLMRFLPTEAEVKLLRQYERERQPLEELAAEDRFMLLFSKV
  ERLTQRMAGMAFLGNFQDNLQMLTPQLNAIIAASASVKSSQKLKQMLEIILALGNYMNSS
  KRGAVYGFKLQSLDLLLDTKSTDRKMTLLHFIALTVKEKYPDLANFWHELHFVEKAAAVS
  LENVLLDVKELGRGMELIRRECSIHDNSVLRNFLSTNEGKLDKLQRDAKTAEEAYNAVVR
  YFGESPKTTPPSVFFPVFVRFIRSYKEAEQENEARKKQEEVMREKQLAQEAKKLDAKTPS
  QRNKWQQQELIAELRRRQAKEHRPVYEGKDGTIEDIITVLKSVPFTARTAKRGSRFFCDA
  AHHDESNC
• Function: Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Required for developmental angiogenesis. In this process, required for microtubule reorganization and for efficient endothelial cell elongation. In quiescent endothelial cells, triggers rearrangement of the actin cytoskeleton, but does not alter microtubule alignement.
• Tissue Specificity: Expressed in endothelial cells.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[3]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Formin-like protein 3 (FMNL3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Formin-like protein 3 (FMNL3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Formin-like protein 3 (FMNL3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Formin-like protein 3 (FMNL3).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Formin-like protein 3 (FMNL3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Formin-like protein 3 (FMNL3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Formin-like protein 3 (FMNL3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Formin-like protein 3 (FMNL3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Formin-like protein 3 (FMNL3).	[8]

References

• [1] High expression of FMNL3 associates with cancer cell migration, invasion, and unfavorable prognosis in tongue squamous cell carcinoma.J Oral Pathol Med. 2019 Jul;48(6):459-467. doi: 10.1111/jop.12857. Epub 2019 Apr 25.
• [2] MicroRNA-127 is a tumor suppressor in human esophageal squamous cell carcinoma through the regulation of oncogene FMNL3.Eur J Pharmacol. 2016 Nov 15;791:603-610. doi: 10.1016/j.ejphar.2016.09.025. Epub 2016 Sep 17.
• [3] Formin-like 3 regulates RhoC/FAK pathway and actin assembly to promote cell invasion in colorectal carcinoma.World J Gastroenterol. 2018 Sep 14;24(34):3884-3897. doi: 10.3748/wjg.v24.i34.3884.
• [4] High FMNL3 expression promotes nasopharyngeal carcinoma cell metastasis: role in TGF-1-induced epithelia-to-mesenchymal transition.Sci Rep. 2017 Feb 15;7:42507. doi: 10.1038/srep42507.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [13] 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.