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beta-secretase 2

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Target not currently curated in GtoImmuPdb

Target id: 2331

Nomenclature: beta-secretase 2

Abbreviated Name: BACE2

Family: A1: Pepsin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 518 21q22.2-q22.3 BACE2 beta-secretase 2
Mouse 1 514 16 C4 Bace2 beta-site APP-cleaving enzyme 2
Rat 1 514 11q12 Bace2 beta-secretase 2
Previous and Unofficial Names Click here for help
AEPLC | ALP56 | ARP1 | asp 1 | ASP21 | aspartyl protease 1 | BAE2 | beta-site amyloid precursor protein cleaving enzyme 2 | beta-site APP-cleaving enzyme 2 | CEAP1 | DRAP | memapsin-1 | theta-secretase
Database Links Click here for help
Specialist databases
MEROPS A01.041 (Hs)
Other databases
Alphafold Q9Y5Z0 (Hs), Q9JL18 (Mm), Q6IE75 (Rn)
BRENDA 3.4.23.45
CATH/Gene3D 2.40.70.10
ChEMBL Target CHEMBL2525 (Hs), CHEMBL3638357 (Mm), CHEMBL2331066 (Rn)
Ensembl Gene ENSG00000182240 (Hs), ENSMUSG00000040605 (Mm), ENSRNOG00000001953 (Rn)
Entrez Gene 25825 (Hs), 56175 (Mm), 288227 (Rn)
Human Protein Atlas ENSG00000182240 (Hs)
KEGG Enzyme 3.4.23.45
KEGG Gene hsa:25825 (Hs), mmu:56175 (Mm), rno:288227 (Rn)
OMIM 605668 (Hs)
Pharos Q9Y5Z0 (Hs)
RefSeq Nucleotide NM_138992 (Hs), NM_012105 (Hs), NM_138991 (Hs), NM_019517 (Mm), NM_001002802 (Rn)
RefSeq Protein NP_620477 (Hs), NP_036237 (Hs), NP_620476 (Hs), NP_062390 (Mm), NP_001002802 (Rn)
UniProtKB Q9Y5Z0 (Hs), Q9JL18 (Mm), Q6IE75 (Rn)
Wikipedia BACE2 (Hs)
Enzyme Reaction Click here for help
EC Number: 3.4.23.45

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 3 [PMID: 27347366] Small molecule or natural product Primary target of this compound Hs Inhibition 10.5 pKi 6
⤷ pKi 10.5 (Ki 3.1x10-11 M) [6]
verubecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.4 – 9.9 pKi 16,18
⤷ pKi 9.9 (Ki 1.2x10-10 M) [18]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
pKi 9.4 (Ki 3.7x10-10 M) [16]
compound 3l [PMID: 30637955] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pKi 4
⤷ pKi 8.8 (Ki 1.6x10-9 M) [4]
atabecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pKi 18
⤷ pKi 8.0 (Ki 9.6x10-9 M) [18]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
compound 6 [PMID: 34553947] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - 6.7 pKi 18
⤷ pKi 6.7 (Ki 1.85x10-7 M) [18]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
β-secretase inhibitor IV Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pKi 5
⤷ pKi 6.6 (Ki 2.4x10-7 M) [5]
example 41 [WO2012028563] Small molecule or natural product Primary target of this compound Hs Inhibition 10.0 pIC50 9
⤷ pIC50 10.0 (IC50 1x10-10 M) [9]
example 98 [WO2011020806] Small molecule or natural product Primary target of this compound Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
example 2 [WO2013004676] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 2
⤷ pIC50 8.7 (IC50 2x10-9 M) [2]
example 92 [WO2012095521] Small molecule or natural product Hs Inhibition 8.4 pIC50 15
⤷ pIC50 8.4 (IC50 4x10-9 M) [15]
NB-360 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 10
⤷ pIC50 8.3 (IC50 5x10-9 M) [10]
example 20 [WO2010128058] Small molecule or natural product Primary target of this compound Hs Inhibition 8.2 pIC50 1
⤷ pIC50 8.2 (IC50 6x10-9 M) [1]
Description: Fluorescent-peptide cleavage assay for BACE2 inhibition.
compound J [PMID: 21907142] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.2 pIC50 3
⤷ pIC50 8.2 (IC50 6x10-9 M) [3]
AM-6494 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pIC50 13
⤷ pIC50 7.7 (IC50 1.86x10-8 M) [13]
umibecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 8
⤷ pIC50 7.5 (IC50 3x10-8 M) [8]
RO5508887 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 7
⤷ pIC50 7.4 (IC50 4x10-8 M) [7]
JNJ-67569762 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pIC50 14
⤷ pIC50 6.7 (IC50 1.95x10-7 M) [14]
hydroxyethylamine transition-state inhibitor 1 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.2 pIC50 12
⤷ pIC50 6.2 (IC50 7x10-7 M) [12]
Immuno Process Associations
Immuno Process:  Inflammation
General Comments
The diabetes drug target validation status for this enzyme is unclear [11].

References

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1. Banner D et.al. (2010) Dihydropyrimidinones for use as BACE2 inhibitors. Patent number: WO2010128058. Assignee: Roche. Priority date: 31/10/2014. Publication date: 11/11/2010.

2. Blass B. (2013) Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett, 4 (4): 379-80. [PMID:24900681]

3. Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, Prummer M, Schmidt A et al.. (2011) Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metab, 14 (3): 365-77. [PMID:21907142]

4. Ghosh AK, Brindisi M, Yen YC, Lendy EK, Kovela S, Cárdenas EL, Reddy BS, Rao KV, Downs D, Huang X et al.. (2019) Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies. ChemMedChem, 14 (5): 545-560. [PMID:30637955]

5. Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu X, Chang W, Weerasena V, Turner R, Koelsch G, Bilcer G et al.. (2007) Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem, 50 (10): 2399-407. [PMID:17432843]

6. Ghosh AK, Reddy BS, Yen YC, Cardenas E, Rao KV, Downs D, Huang X, Tang J, Mesecar AD. (2016) Design of Potent and Highly Selective Inhibitors for Human β-Secretase 2 (Memapsin 1), a Target for Type 2 Diabetes. Chem Sci, 7: 3117-3122. [PMID:27347366]

7. Jacobsen H, Ozmen L, Caruso A, Narquizian R, Hilpert H, Jacobsen B, Terwel D, Tanghe A, Bohrmann B. (2014) Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci, 34 (35): 11621-30. [PMID:25164658]

8. Machauer R, Lueoend R, Hurth K, Veenstra SJ, Rueeger H, Voegtle M, Tintelnot-Blomley M, Rondeau JM, Jacobson LH, Laue G et al.. (2021) Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease. J Med Chem, 64 (20): 15262-15279. [PMID:34648711]

9. Mauser H etal. (2012) Bace inhibitors for use in the treatment of diabetes. Patent number: WO2012028563. Assignee: Roche. Priority date: 01/09/2009. Publication date: 08/03/2012.

10. Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P et al.. (2015) A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice. Mol Neurodegener, 10: 44. [PMID:26336937]

11. O'Donnell P et al. BACE1/2 inhibition does not regulate pancreatic beta cell function and mass in mice. Accessed on 07/08/2015. Modified on 07/08/2015. Alzheimers and Dementia, http://www.alzheimersanddementia.com/article/S1552-5260%2814%2901380-6/fulltext. DOI: 10.1016/j.jalz.2014.05.733

12. Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B. (2006) Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. J Mol Biol, 355 (2): 249-61. [PMID:16305800]

13. Pettus LH, Bourbeau MP, Bradley J, Bartberger MD, Chen K, Hickman D, Johnson M, Liu Q, Manning JR, Nanez A et al.. (2020) Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2. J Med Chem, 63 (5): 2263-2281. [PMID:31589043]

14. Rombouts FJR, Kusakabe KI, Alexander R, Austin N, Borghys H, De Cleyn M, Dhuyvetter D, Gijsen HJM, Hrupka B, Jacobs T et al.. (2021) JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate. J Med Chem, 64 (19): 14175-14191. [PMID:34553934]

15. Rueeger H et al.. (2012) Bace-2 inhibitors for the treatment of metabolic disorders. Patent number: WO2012095521. Assignee: Novartis. Priority date: 03/01/2011. Publication date: 19/07/2012.

16. Scott JD et al.. (2015) Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use. Patent number: US8940748. Assignee: Merck Sharp & Dohme. Priority date: 08/10/2009. Publication date: 27/01/2015.

17. Southan C. (2013) BACE2 as a new diabetes target: a patent review (2010 - 2012). Expert Opin Ther Pat, 23 (5): 649-63. [PMID:23506624]

18. Ueno T, Matsuoka E, Asada N, Yamamoto S, Kanegawa N, Ito M, Ito H, Moechars D, Rombouts FJR, Gijsen HJM et al.. (2021) Discovery of Extremely Selective Fused Pyridine-Derived β-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions. J Med Chem, 64 (19): 14165-14174. [PMID:34553947]

How to cite this page

A1: Pepsin: beta-secretase 2. Last modified on 12/06/2023. Accessed on 19/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2331.