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beta-secretase 1

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Target id: 2330

Nomenclature: beta-secretase 1

Abbreviated Name: BACE1

Family: A1: Pepsin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 501 11q23.3 BACE1 beta-secretase 1
Mouse 1 501 9 A5.2 Bace1 beta-site APP cleaving enzyme 1
Rat 1 501 8q22 Bace1 beta-secretase 1
Previous and Unofficial Names Click here for help
ASP2 | APP beta-secretase | aspartyl protease 2 | Bace | beta-site amyloid precursor protein cleaving enzyme 1 | memapsin-2 | beta-site APP-cleaving enzyme 1
Database Links Click here for help
Specialist databases
MEROPS A01.004 (Hs)
Other databases
Alphafold P56817 (Hs), P56818 (Mm), P56819 (Rn)
BRENDA 3.4.23.46
CATH/Gene3D 2.40.70.10
ChEMBL Target CHEMBL4822 (Hs), CHEMBL4593 (Mm), CHEMBL3259473 (Rn)
DrugBank Target P56817 (Hs)
Ensembl Gene ENSG00000186318 (Hs), ENSMUSG00000032086 (Mm), ENSRNOG00000016847 (Rn)
Entrez Gene 23621 (Hs), 23821 (Mm), 29392 (Rn)
Human Protein Atlas ENSG00000186318 (Hs)
KEGG Enzyme 3.4.23.46
KEGG Gene hsa:23621 (Hs), mmu:23821 (Mm), rno:29392 (Rn)
OMIM 604252 (Hs)
Pharos P56817 (Hs)
RefSeq Nucleotide NM_138972 (Hs), NM_138973 (Hs), NM_001207049 (Hs), NM_012104 (Hs), NM_138971 (Hs), NM_001145947 (Mm), NM_011792 (Mm), NM_019204 (Rn)
RefSeq Protein NP_620427 (Hs), NP_620428 (Hs), NP_620429 (Hs), NP_001193978 (Hs), NP_036236 (Hs), NP_001139419 (Mm), NP_035922 (Mm), NP_062077 (Rn)
SynPHARM 84541 (in complex with AMG-8718)
78987 (in complex with AZ-4217)
82636 (in complex with compound 16 [PMID: 23412139])
79000 (in complex with compound 2 [PMID: 22911925])
78985 (in complex with LY2811376)
78477 (in complex with LY2886721)
78993 (in complex with oxazine 89)
84891 (in complex with RO5508887)
UniProtKB P56817 (Hs), P56818 (Mm), P56819 (Rn)
Wikipedia BACE1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Co-crystal structure of BACE with inhibitor AM-6494
PDB Id:  6PZ4
Ligand:  AM-6494
Resolution:  1.85Å
Species:  Human
References:  23
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide
PDB Id:  7F1D
Ligand:  compound 6 [PMID: 34553947]
Resolution:  2.05Å
Species:  Human
References:  29
Enzyme Reaction Click here for help
EC Number: 3.4.23.46

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 6 [PMID: 34553947] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.9 pKi 29
⤷ pKi 9.9 (Ki 1.3x10-10 M) [29]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
verubecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Competitive 8.8 – 9.5 pKi 27,29
⤷ pKi 9.5 (Ki 3.4x10-10 M) [29]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
pKi 8.8 (Ki 1.753x10-9 M) [27]
atabecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.1 pKi 29
⤷ pKi 9.1 (Ki 8x10-10 M) [29]
Description: BInding affinity determined in a competitive radioligand binding assay using the nonselective BACE1/2 inhibitor [3H] JNJ-962
compound 16 [PMID: 23412139] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 8.8 pKi 28
⤷ pKi 8.8 (Ki 1.7x10-9 M) [28]
AZ-4217 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 8.7 pKi 5
⤷ pKi 8.7 (Ki 1.8x10-9 M) [5]
compound 9 [PMID: 26937601] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.3 pKi 17
⤷ pKi 8.3 (Ki 5x10-9 M) [17]
Description: Inhibition of recombinant hBACE1 by FRET assay; substrate QSY7EISEVNLDAEFC-Eu-amide
compound 13 [PMID: 23412139] Small molecule or natural product Primary target of this compound Hs Inhibition 8.1 pKi 28
⤷ pKi 8.1 (Ki 7.8x10-9 M) [28]
AZD3839 Small molecule or natural product Primary target of this compound Hs Competitive 7.6 pKi 13
⤷ pKi 7.6 (Ki 2.61x10-8 M) [13]
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 9
⤷ pKi 6.6 (Ki 2.33x10-7 M) [9]
compound 3l [PMID: 30637955] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.1 pKi 8
⤷ pKi 6.1 (Ki 8.151x10-7 M) [8]
TAK-070 Small molecule or natural product Primary target of this compound Hs Non-competitive 4.7 pKi 7
⤷ pKi 4.7 (Ki 1.9x10-5 M) [7]
compound 15 [PMID: 25699151] Small molecule or natural product Primary target of this compound Hs Inhibition 9.5 pIC50 3
⤷ pIC50 9.5 (IC50 3x10-10 M) [3]
AM-6494 Small molecule or natural product Ligand has a PDB structure Mm Inhibition 9.4 pIC50 23
⤷ pIC50 9.4 (IC50 3.6x10-10 M) [23]
AM-6494 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.4 pIC50 23
⤷ pIC50 9.4 (IC50 4x10-10 M) [23]
AM-6494 Small molecule or natural product Ligand has a PDB structure Rn Inhibition 9.2 pIC50 23
⤷ pIC50 9.2 (IC50 6.2x10-10 M) [23]
AMG-8718 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 9.1 pIC50 4
⤷ pIC50 9.1 (IC50 7x10-10 M) [4]
PF-06684511 Small molecule or natural product Primary target of this compound Hs Inhibition 9.1 pIC50 31
⤷ pIC50 9.1 (IC50 7x10-10 M) [31]
lanabecestat Small molecule or natural product Primary target of this compound Hs Competitive 8.7 pIC50 1
⤷ pIC50 8.7 (IC50 2.2x10-9 M) [1]
JNJ-67569762 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 25
⤷ pIC50 8.6 (IC50 2.7x10-9 M) [25]
compound 11d [PMID: 23981898] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 8.4 pIC50 26
⤷ pIC50 8.4 (IC50 4x10-9 M) [26]
NB-360 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 21
⤷ pIC50 8.3 (IC50 5x10-9 M) [21]
compound 2 [PMID: 22911925] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 8.3 pIC50 30
⤷ pIC50 8.3 (IC50 5.5x10-9 M) [30]
elenbecestat Small molecule or natural product Primary target of this compound Hs Inhibition 8.1 pIC50 14
⤷ pIC50 8.1 (IC50 7x10-9 M) [14]
PF-06751979 Small molecule or natural product Hs Inhibition 8.1 pIC50 22
⤷ pIC50 8.1 (IC50 7.3x10-9 M) [22]
atabecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 15
⤷ pIC50 8.0 (IC50 9.8x10-9 M) [15]
umibecestat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 16
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [16]
oxazine 89 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 7.9 pIC50 10
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [10]
compound J [PMID: 21907142] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [6]
LY2886721 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 7.7 pIC50 18
⤷ pIC50 7.7 (IC50 2.03x10-8 M) [18]
example 2 [WO2013004676] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pIC50 2
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [2]
AZ3971 Small molecule or natural product Primary target of this compound Hs Competitive 7.5 pIC50 11
⤷ pIC50 7.5 (IC50 3x10-8 M) [11]
RO5508887 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 12
⤷ pIC50 7.5 (IC50 3x10-8 M) [12]
LY2811376 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 6.6 pIC50 19
⤷ pIC50 6.6 (IC50 2.39x10-7 M) [19]
LY3202626 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.2 pIC50 20
⤷ pIC50 6.2 (IC50 6.15x10-7 M) [20]
Description: Inhibition of BACE1 enzyme activity in a biochemical assay.
Compound 12 [PMID:28626832] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 3.3 pIC50 24
⤷ pIC50 3.3 (IC50 5x10-4 M) [24]
View species-specific inhibitor tables

References

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1. Blass B. (2012) Compounds and Their Use as BACE Inhibitors: Patent Highlight. ACS Med Chem Lett, 3 (11): 875-6. [PMID:24900397]

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. Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn 2nd RT et al.. (2015) An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities. ACS Med Chem Lett, 6 (2): 210-5. [PMID:25699151]

4. Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC et al.. (2014) Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718). J Med Chem, 57 (23): 9811-31. [PMID:25363711]

5. Eketjäll S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K, Gustavsson S, Radesäter AC, Eliason K, Briem S, Appelkvist P et al.. (2013) AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J Neurosci, 33 (24): 10075-84. [PMID:23761903]

6. 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]

7. Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M, Sagayama M, Maeda R, Kawamoto M, Hirai K et al.. (2010) A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci, 30 (33): 11157-66. [PMID:20720123]

8. 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]

9. 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]

10. Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D et al.. (2013) β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J Med Chem, 56 (10): 3980-95. [PMID:23590342]

11. Holenz J et al. (2011) 5h-pyrrolo[3,4- gbp >]pyrazin-7-amine derivatives inhibitors of beta-secretase. Patent number: WO2011002409. Assignee: AstraZeneca. Priority date: 03/07/2009. Publication date: 06/01/2011.

12. 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]

13. Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K et al.. (2012) Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem, 287 (49): 41245-57. [PMID:23048024]

14. Juichi, S et al.. (2009) Fused aminodihydrothiazine derivatives. Patent number: US20090209755. Assignee: Eisai. Priority date: 18/01/2008. Publication date: 20/08/2009.

15. Koriyama, Y. Discovery and synthesis of JNJ-​54861911, a novel orally active BACE1 inhibitor. Accessed on 28/05/2018. Modified on 28/05/2018. CiteUlike, http://www.citeulike.org/user/cdsouthan/article/14595136

16. 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]

17. Mandal M, Wu Y, Misiaszek J, Li G, Buevich A, Caldwell JP, Liu X, Mazzola RD, Orth P, Strickland C et al.. (2016) Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates. J Med Chem, 59 (7): 3231-48. [PMID:26937601]

18. May P, Boggs L, Brier R, Calligaro D, Citron M, Day T, Lin S, Lindstrom T, Mergott D, Monk S et al.. (2012) Preclinical characterizathion of LY2886721: A BACE1 inhibitor in clinical development for early Alzheimer's disease. Alzheimers Dement, 8 (4): 95.

19. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM et al.. (2011) Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci, 31 (46): 16507-16. [PMID:22090477]

20. McKinzie DL, Winneroski LL, Green SJ, Hembre EJ, Erickson JA, Willis BA, Monk SA, Aluise CD, Baker TK, Lopez JE et al.. (2021) Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor. J Med Chem, 64 (12): 8076-8100. [PMID:34081466]

21. 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]

22. O'Neill BT, Beck EM, Butler CR, Nolan CE, Gonzales C, Zhang L, Doran SD, Lapham K, Buzon LM, Dutra JK et al.. (2018) Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J Med Chem, 61 (10): 4476-4504. [PMID:29613789]

23. 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]

24. Rombouts FJR, Alexander R, Cleiren E, De Groot A, Carpentier M, Dijkmans J, Fierens K, Masure S, Moechars D, Palomino-Schätzlein M et al.. (2017) Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches. ACS Omega, 2 (2): 685-697. [PMID:28626832]

25. 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]

26. Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Möbitz H, Neumann U. (2013) Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides. Bioorg Med Chem Lett, 23 (19): 5300-6. [PMID:23981898]

27. 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.

28. Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ et al.. (2012) Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction. ACS Med Chem Lett, 3 (11): 897-902. [PMID:23412139]

29. 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]

30. Wood S, Wen PH, Zhang J, Zhu L, Luo Y, Babu-Khan S, Chen K, Pham R, Esmay J, Dineen TA et al.. (2012) Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived β-secretase inhibitors. J Pharmacol Exp Ther, 343 (2): 460-7. [PMID:22911925]

31. Zhang L, Chen L, Dutra JK, Beck EM, Nag S, Takano A, Amini N, Arakawa R, Brodney MA, Buzon LM et al.. (2018) Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain. J Med Chem, 61 (8): 3296-3308. [PMID:29356535]

How to cite this page

A1: Pepsin: beta-secretase 1. Last modified on 24/11/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2330.