Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOA7ON7)

• DOT Name: Kin of IRRE-like protein 1 (KIRREL1)
• Synonyms: Kin of irregular chiasm-like protein 1; Nephrin-like protein 1
• Gene Name: KIRREL1
• Related Disease:
  Steroid-resistant nephrotic syndrome
  Focal segmental glomerulosclerosis
  Nephrotic syndrome
  Pulmonary arterial hypertension
  Gastrointestinal stromal tumour
  Gastric cancer
  Nephrotic syndrome, type 23
  Osteosarcoma
  Stomach cancer
• UniProt ID: KIRR1_HUMAN
• Pfam ID: PF08205 ; PF07679 ; PF13927
• Sequence:
  MLSLLVWILTLSDTFSQGTQTRFSQEPADQTVVAGQRAVLPCVLLNYSGIVQWTKDGLAL
  GMGQGLKAWPRYRVVGSADAGQYNLEITDAELSDDASYECQATEAALRSRRAKLTVLIPP
  EDTRIDGGPVILLQAGTPHNLTCRAFNAKPAATIIWFRDGTQQEGAVASTELLKDGKRET
  TVSQLLINPTDLDIGRVFTCRSMNEAIPSGKETSIELDVHHPPTVTLSIEPQTVQEGERV
  VFTCQATANPEILGYRWAKGGFLIEDAHESRYETNVDYSFFTEPVSCEVHNKVGSTNVST
  LVNVHFAPRIVVDPKPTTTDIGSDVTLTCVWVGNPPLTLTWTKKDSNMVLSNSNQLLLKS
  VTQADAGTYTCRAIVPRIGVAEREVPLYVNGPPIISSEAVQYAVRGDGGKVECFIGSTPP
  PDRIAWAWKENFLEVGTLERYTVERTNSGSGVLSTLTINNVMEADFQTHYNCTAWNSFGP
  GTAIIQLEEREVLPVGIIAGATIGASILLIFFFIALVFFLYRRRKGSRKDVTLRKLDIKV
  ETVNREPLTMHSDREDDTASVSTATRVMKAIYSSFKDDVDLKQDLRCDTIDTREEYEMKD
  PTNGYYNVRAHEDRPSSRAVLYADYRAPGPARFDGRPSSRLSHSSGYAQLNTYSRGPASD
  YGPEPTPPGPAAPAGTDTTSQLSYENYEKFNSHPFPGAAGYPTYRLGYPQAPPSGLERTP
  YEAYDPIGKYATATRFSYTSQHSDYGQRFQQRMQTHV
• Function: Required for proper function of the glomerular filtration barrier. It is involved in the maintenance of a stable podocyte architecture with interdigitating foot processes connected by specialized cell-cell junctions, known as the slit diaphragm. It is a signaling protein that needs the presence of TEC kinases to fully trans-activate the transcription factor AP-1.
• Tissue Specificity: Abundantly expressed in kidney. Specifically expressed in podocytes of kidney glomeruli.
• Reactome Pathway: Nephrin family interactions (R-HSA-373753)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Steroid-resistant nephrotic syndrome	DISVEBC9	Definitive	Genetic Variation	[1]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[2]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[3]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[4]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[5]
Gastric cancer	DISXGOUK	Limited	Biomarker	[6]
Nephrotic syndrome, type 23	DISRSCA0	Limited	Unknown	[7]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[8]
Stomach cancer	DISKIJSX	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kin of IRRE-like protein 1 (KIRREL1).	[15]

References

• [1] Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome.Kidney Int. 2019 Oct;96(4):883-889. doi: 10.1016/j.kint.2019.06.016. Epub 2019 Jul 10.
• [2] Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin.J Clin Invest. 2006 May;116(5):1337-45. doi: 10.1172/JCI27400. Epub 2006 Apr 20.
• [3] Interaction of CD80 with Neph1: a potential mechanism of podocyte injury.Clin Exp Nephrol. 2018 Jun;22(3):508-516. doi: 10.1007/s10157-017-1489-3. Epub 2017 Oct 11.
• [4] Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function.Sci Rep. 2017 Sep 21;7(1):12047. doi: 10.1038/s41598-017-12134-8.
• [5] Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA.Cancer Med. 2013 Feb;2(1):21-31. doi: 10.1002/cam4.57. Epub 2013 Feb 3.
• [6] Overexpression of Kin of IRRE-Like Protein 1 (KIRREL) in Gastric Cancer and Its Clinical Prognostic Significance.Med Sci Monit. 2018 May 2;24:2711-2719. doi: 10.12659/MSM.910386.
• [7] Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant. 2006 Nov;21(11):3133-8. doi: 10.1093/ndt/gfl347. Epub 2006 Sep 12.
• [8] CpG methylation patterns are associated with gene expression variation in osteosarcoma.Mol Med Rep. 2017 Jul;16(1):901-907. doi: 10.3892/mmr.2017.6635. Epub 2017 May 26.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] 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.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.