Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCA7B6A)

• DOT Name: Beta-secretase 1 (BACE1)
• Synonyms: EC 3.4.23.46; Aspartyl protease 2; ASP2; Asp 2; Beta-site amyloid precursor protein cleaving enzyme 1; Beta-site APP cleaving enzyme 1; Memapsin-2; Membrane-associated aspartic protease 2
• Gene Name: BACE1
• UniProt ID: BACE1_HUMAN
• PDB ID: 1FKN ; 1M4H ; 1PY1 ; 1SGZ ; 1TQF ; 1UJJ ; 1UJK ; 1W50 ; 1W51 ; 1XN2 ; 1XN3 ; 1XS7 ; 1YM2 ; 1YM4 ; 2B8L ; 2B8V ; 2F3E ; 2F3F ; 2FDP ; 2G94 ; 2HIZ ; 2HM1 ; 2IQG ; 2IRZ ; 2IS0 ; 2NTR ; 2OAH ; 2OF0 ; 2OHK ; 2OHL ; 2OHM ; 2OHN ; 2OHP ; 2OHQ ; 2OHR ; 2OHS ; 2OHT ; 2OHU ; 2P4J ; 2P83 ; 2P8H ; 2PH6 ; 2PH8 ; 2Q11 ; 2Q15 ; 2QK5 ; 2QMD ; 2QMF ; 2QMG ; 2QP8 ; 2QU2 ; 2QU3 ; 2QZK ; 2QZL ; 2VA5 ; 2VA6 ; 2VA7 ; 2VIE ; 2VIJ ; 2VIY ; 2VIZ ; 2VJ6 ; 2VJ7 ; 2VJ9 ; 2VKM ; 2VNM ; 2VNN ; 2WEZ ; 2WF0 ; 2WF1 ; 2WF2 ; 2WF3 ; 2WF4 ; 2WJO ; 2XFI ; 2XFJ ; 2XFK ; 2ZDZ ; 2ZE1 ; 2ZHR ; 2ZHS ; 2ZHT ; 2ZHU ; 2ZHV ; 2ZJH ; 2ZJI ; 2ZJJ ; 2ZJK ; 2ZJL ; 2ZJM ; 2ZJN ; 3BRA ; 3BUF ; 3BUG ; 3BUH ; 3CIB ; 3CIC ; 3CID ; 3CKP ; 3CKR ; 3DM6 ; 3DUY ; 3DV1 ; 3DV5 ; 3EXO ; 3FKT ; 3H0B ; 3HVG ; 3HW1 ; 3I25 ; 3IGB ; 3IN3 ; 3IN4 ; 3IND ; 3INE ; 3INF ; 3INH ; 3IVH ; 3IVI ; 3IXJ ; 3IXK ; 3K5C ; 3K5D ; 3K5F ; 3K5G ; 3KMX ; 3KMY ; 3KN0 ; 3KYR ; 3L38 ; 3L3A ; 3L58 ; 3L59 ; 3L5B ; 3L5C ; 3L5D ; 3L5E ; 3L5F ; 3LHG ; 3LNK ; 3LPI ; 3LPJ ; 3LPK ; 3MSJ ; 3MSK ; 3MSL ; 3N4L ; 3NSH ; 3OHF ; 3OHH ; 3OOZ ; 3PI5 ; 3QBH ; 3QI1 ; 3R1G ; 3R2F ; 3RSV ; 3RSX ; 3RTH ; 3RTM ; 3RTN ; 3RU1 ; 3RVI ; 3S2O ; 3S7L ; 3S7M ; 3SKF ; 3SKG ; 3TPJ ; 3TPL ; 3TPP ; 3TPR ; 3U6A ; 3UDH ; 3UDJ ; 3UDK ; 3UDM ; 3UDN ; 3UDP ; 3UDQ ; 3UDR ; 3UDY ; 3UFL ; 3UQP ; 3UQR ; 3UQU ; 3UQW ; 3UQX ; 3VEU ; 3VF3 ; 3VG1 ; 3VV6 ; 3VV7 ; 3VV8 ; 3WB4 ; 3WB5 ; 3ZMG ; 3ZOV ; 4ACU ; 4ACX ; 4AZY ; 4B00 ; 4B05 ; 4B0Q ; 4B1C ; 4B1D ; 4B1E ; 4B70 ; 4B72 ; 4B77 ; 4B78 ; 4BEK ; 4BFD ; 4D83 ; 4D85 ; 4D88 ; 4D89 ; 4D8C ; 4DH6 ; 4DI2 ; 4DJU ; 4DJV ; 4DJW ; 4DJX ; 4DJY ; 4DPF ; 4DPI ; 4DUS ; 4DV9 ; 4DVF ; 4EWO ; 4EXG ; 4FCO ; 4FGX ; 4FM7 ; 4FM8 ; 4FRI ; 4FRJ ; 4FRK ; 4FRS ; 4FS4 ; 4FSE ; 4FSL ; 4GID ; 4GMI ; 4H1E ; 4H3F ; 4H3G ; 4H3I ; 4H3J ; 4HA5 ; 4HZT ; 4I0D ; 4I0E ; 4I0F ; 4I0G ; 4I0H ; 4I0I ; 4I0J ; 4I0Z ; 4I10 ; 4I11 ; 4I12 ; 4I1C ; 4IVS ; 4IVT ; 4J0P ; 4J0T ; 4J0V ; 4J0Y ; 4J0Z ; 4J17 ; 4J1C ; 4J1E ; 4J1F ; 4J1H ; 4J1I ; 4J1K ; 4JOO ; 4JP9 ; 4JPC ; 4JPE ; 4K8S ; 4K9H ; 4KE0 ; 4KE1 ; 4L7G ; 4L7H ; 4L7J ; 4LC7 ; 4LXA ; 4LXK ; 4LXM ; 4N00 ; 4PZW ; 4PZX ; 4R5N ; 4R8Y ; 4R91 ; 4R92 ; 4R93 ; 4R95 ; 4RCD ; 4RCE ; 4RCF ; 4RRN ; 4RRO ; 4RRS ; 4TRW ; 4TRY ; 4TRZ ; 4WTU ; 4WY1 ; 4WY6 ; 4X2L ; 4X7I ; 4XKX ; 4XXS ; 4YBI ; 4ZPE ; 4ZPF ; 4ZPG ; 4ZSM ; 4ZSP ; 4ZSQ ; 4ZSR ; 5CLM ; 5DQC ; 5ENK ; 5ENM ; 5EZX ; 5EZZ ; 5F00 ; 5F01 ; 5HD0 ; 5HDU ; 5HDV ; 5HDX ; 5HDZ ; 5HE4 ; 5HE5 ; 5HE7 ; 5HTZ ; 5HU0 ; 5HU1 ; 5I3V ; 5I3W ; 5I3X ; 5I3Y ; 5IE1 ; 5KQF ; 5KR8 ; 5MBW ; 5MCO ; 5MCQ ; 5MXD ; 5QCO ; 5QCP ; 5QCQ ; 5QCR ; 5QCS ; 5QCT ; 5QCU ; 5QCV ; 5QCW ; 5QCX ; 5QCY ; 5QCZ ; 5QD0 ; 5QD1 ; 5QD2 ; 5QD3 ; 5QD4 ; 5QD5 ; 5QD6 ; 5QD7 ; 5QD8 ; 5QD9 ; 5QDA ; 5QDB ; 5QDC ; 5QDD ; 5T1U ; 5T1W ; 5TOL ; 5UYU ; 5V0N ; 5YGX ; 5YGY ; 6BFD ; 6BFE ; 6BFW ; 6BFX ; 6C2I ; 6DHC ; 6DMI ; 6E3Z ; 6EJ2 ; 6EJ3 ; 6EQM ; 6FGY ; 6JSE ; 6JSF ; 6JSG ; 6JSN ; 6JT3 ; 6JT4 ; 6NV7 ; 6NV9 ; 6NW3 ; 6OD6 ; 6PZ4 ; 6UVP ; 6UVV ; 6UVY ; 6UWP ; 6UWV ; 6WNY ; 7B1E ; 7B1P ; 7B1Q ; 7D2V ; 7D2X ; 7D36 ; 7D5A ; 7DCZ ; 7F1D ; 7MYI ; 7MYR ; 7MYU ; 7N66
• EC Number: 3.4.23.46
• Pfam ID: PF00026
• Sequence:
  MAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSF
  VEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSST
  YRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGIL
  GLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGI
  DHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKK
  VFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRIT
  ILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSAC
  HVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQW
  RCLRCLRQQHDDFADDISLLK
• Function: Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Cleaves CHL1.
• Tissue Specificity: Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata.
• KEGG Pathway: Alzheimer disease (hsa05010)
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)
• BioCyc Pathway: MetaCyc:ENSG00000160610-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 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 Beta-secretase 1 (BACE1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-secretase 1 (BACE1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Beta-secretase 1 (BACE1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-secretase 1 (BACE1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Beta-secretase 1 (BACE1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Beta-secretase 1 (BACE1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Beta-secretase 1 (BACE1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Beta-secretase 1 (BACE1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Beta-secretase 1 (BACE1).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Beta-secretase 1 (BACE1).	[10]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Beta-secretase 1 (BACE1).	[11]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Beta-secretase 1 (BACE1).	[11]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Beta-secretase 1 (BACE1).	[12]
Trientine	DMD2WPG	Approved	Trientine decreases the expression of Beta-secretase 1 (BACE1).	[13]
Isoflurane	DMY6T31	Approved	Isoflurane increases the expression of Beta-secretase 1 (BACE1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Beta-secretase 1 (BACE1).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Beta-secretase 1 (BACE1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beta-secretase 1 (BACE1).	[16]
HY-N2258	DML4IAX	Preclinical	HY-N2258 decreases the activity of Beta-secretase 1 (BACE1).	[5]
Manganese	DMKT129	Investigative	Manganese increases the expression of Beta-secretase 1 (BACE1).	[18]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol increases the expression of Beta-secretase 1 (BACE1).	[19]
MEMOQUIN	DM9S30P	Investigative	MEMOQUIN decreases the activity of Beta-secretase 1 (BACE1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Beta-secretase 1 (BACE1).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate affects the localization of Beta-secretase 1 (BACE1).	[20]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Flavanone glycosides inhibit -site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce A aggregation in the amyloidogenic pathway. Chem Biol Interact. 2019 Aug 25;309:108707. doi: 10.1016/j.cbi.2019.06.020. Epub 2019 Jun 11.
• [6] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [7] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [11] Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003 Oct 29;23(30):9796-804. doi: 10.1523/JNEUROSCI.23-30-09796.2003.
• [12] The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol. 2009 May;66(5):620-31. doi: 10.1001/archneurol.2009.48.
• [13] Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-B pathway in a transgenic mouse model of Alzheimer's disease. Antioxid Redox Signal. 2013 Dec 10;19(17):2024-39. doi: 10.1089/ars.2012.5158. Epub 2013 May 3.
• [14] The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007 Feb 7;27(6):1247-54. doi: 10.1523/JNEUROSCI.5320-06.2007.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by curcumin. Neurosci Lett. 2008 Aug 8;440(3):344-7. doi: 10.1016/j.neulet.2008.05.070. Epub 2008 May 24.
• [19] Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol Neurodegener. 2009 Jan 6;4:1. doi: 10.1186/1750-1326-4-1.
• [20] Regulation of secretases by all-trans-retinoic acid. FEBS J. 2009 May;276(9):2645-55. doi: 10.1111/j.1742-4658.2009.06992.x. Epub 2009 Mar 25.
• [21] Synthesis of monomeric derivatives to probe memoquin's bivalent interactions. J Med Chem. 2011 Dec 22;54(24):8299-304.