Details of Drug Off-Target (DOT)

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

• DOT Name: Actin filament-associated protein 1-like 1 (AFAP1L1)
• Synonyms: AFAP1-like protein 1
• Gene Name: AFAP1L1
• Related Disease:
  Colorectal carcinoma
  Malignant soft tissue neoplasm
  Non-small-cell lung cancer
  Rectal carcinoma
  Sarcoma
• UniProt ID: AF1L1_HUMAN
• Pfam ID: PF00169
• Sequence:
  MDRGQVLEQLLPELTGLLSLLDHEYLSDTTLEKKMAVASILQSLQPLPAKEVSYLYVNTA
  DLHSGPSFVESLFEEFDCDLSDLRDMPEDDGEPSKGASPELAKSPRLRNAADLPPPLPNK
  PPPEDYYEEALPLGPGKSPEYISSHNGCSPSHSIVDGYYEDADSSYPATRVNGELKSSYN
  DSDAMSSSYESYDEEEEEGKSPQPRHQWPSEEASMHLVRECRICAFLLRKKRFGQWAKQL
  TVIREDQLLCYKSSKDRQPHLRLALDTCSIIYVPKDSRHKRHELRFTQGATEVLVLALQS
  REQAEEWLKVIREVSKPVGGAEGVEVPRSPVLLCKLDLDKRLSQEKQTSDSDSVGVGDNC
  STLGRRETCDHGKGKKSSLAELKGSMSRAAGRKITRIIGFSKKKTLADDLQTSSTEEEVP
  CCGYLNVLVNQGWKERWCRLKCNTLYFHKDHMDLRTHVNAIALQGCEVAPGFGPRHPFAF
  RILRNRQEVAILEASCSEDMGRWLGLLLVEMGSRVTPEALHYDYVDVETLTSIVSAGRNS
  FLYARSCQNQWPEPRVYDDVPYEKMQDEEPERPTGAQVKRHASSCSEKSHRVDPQVKVKR
  HASSANQYKYGKNRAEEDARRYLVEKEKLEKEKETIRTELIALRQEKRELKEAIRSSPGA
  KLKALEEAVATLEAQCRAKEERRIDLELKLVAVKERLQQSLAGGPALGLSVSSKPKSGET
  ANKPQNSVPEQPLPVNCVSELRKRSPSIVASNQGRVLQKAKEWEMKKT
• Function: May be involved in podosome and invadosome formation.
• Tissue Specificity: Expressed in breast, colon and brain. In all 3 tissues, expressed in the microvasculature (at protein level). In addition, in the breast, found in the contractile myoepithelial cell layer which surrounds the breast ducts (at protein level). In the colon, expressed in the mucous membrane and colonic crypts and in the smooth muscle cell layer which provide movement of the colon (at protein level). In the cerebellum, localized around the Purkinje neurons and the granule cells of the granular layer, but not inside cell bodies (at protein level). Outside of the cerebellar cortex, expressed in glial cells (at protein level). Highly expressed away from the cell bodies within the dentate nucleus (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Rectal carcinoma	DIS8FRR7	Strong	Altered Expression	[1]
Sarcoma	DISZDG3U	Strong	Biomarker	[2]

11 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 Actin filament-associated protein 1-like 1 (AFAP1L1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Actin filament-associated protein 1-like 1 (AFAP1L1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Actin filament-associated protein 1-like 1 (AFAP1L1).	[12]

References

• [1] AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers.Cancer Med. 2014 Aug;3(4):759-74. doi: 10.1002/cam4.237. Epub 2014 Apr 10.
• [2] Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas.Oncogene. 2011 Sep 22;30(38):4015-25. doi: 10.1038/onc.2011.108. Epub 2011 Apr 25.
• [3] Actin Filament-Associated Protein 1-Like 1 Mediates Proliferation and Survival in Non-Small Cell Lung Cancer Cells.Med Sci Monit. 2018 Jan 11;24:215-224. doi: 10.12659/msm.905900.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [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.
• [14] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [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.