Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8GUMV)

• DOT Name: Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2)
• Synonyms: LRR FLII-interacting protein 2
• Gene Name: LRRFIP2
• Related Disease:
  Advanced cancer
  Hereditary nonpolyposis colon cancer
  Lynch syndrome
• UniProt ID: LRRF2_HUMAN
• Pfam ID: PF09738
• Sequence:
  MGTPASGRKRTPVKDRFSAEDEALSNIAREAEARLAAKRAARAEARDIRMRELERQQKEY
  SLHSFDRKWGQIQKWLEDSERARYSHRSSHHRPYLGVEDALSIRSVGSHRYDMFKDRSSR
  LSSLNHSYSHSHGMKKRSSDSHKDLLSGLYFDQRNYSSLRHSKPTSAYYTRQSSSLYSDP
  LATYKSDRASPTANSGLLRSASLASLYNGGLYNPYGPRTPSECSYYSSRISSARSSPGFT
  NDDTASIVSSDRASRGRRESVVSAADYFSRSNRRGSVVSEVDDISIPDLSSLDEKSDKQY
  AENYTRPSSRNSASATTPLSGNSSRRGSGDTSSLIDPDTSLSELRDIYDLKDQIQDVEGR
  YMQGLKELKESLSEVEEKYKKAMVSNAQLDNEKNNLIYQVDTLKDVIEEQEEQMAEFYRE
  NEEKSKELERQKHMCSVLQHKMEELKEGLRQRDELIEEKQRMQQKIDTMTKEVFDLQETL
  LWKDKKIGALEKQKEYIACLRNERDMLREELADLQETVKTGEKHGLVIIPDGTPNGDVSH
  EPVAGAITVVSQEAAQVLESAGEGPLDVRLRKLAGEKEELLSQIRKLKLQLEEERQKCSR
  NDGTVGDLAGLQNGSDLQFIEMQRDANRQISEYKFKLSKAEQDITTLEQSISRLEGQVLR
  YKTAAENAEKVEDELKAEKRKLQRELRTALDKIEEMEMTNSHLAKRLEKMKANRTALLAQ
  Q
• Function: May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.
• Tissue Specificity: Widely expressed, with highest levels in heart and skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Genetic Variation	[2]
Lynch syndrome	DIS3IW5F	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2).	[10]

References

• [1] An interstitial deletion at 3p21.3 results in the genetic fusion of MLH1 and ITGA9 in a Lynch syndrome family.Clin Cancer Res. 2009 Feb 1;15(3):762-9. doi: 10.1158/1078-0432.CCR-08-1908.
• [2] A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families.Genet Med. 2011 Oct;13(10):895-902. doi: 10.1097/GIM.0b013e31821dd525.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.