Target Information

Target General Information

Target ID

T73992 (Former ID: TTDC00092)

Target Name

Beta-secretase (BACE)

Synonyms

Transmembrane aspartic protease; Beta-site amyloid precursor protein cleaving enzyme; Beta-site AbetaPP-cleaving enzyme; BACE1

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Gene Name

NO-GeName

Target Type

Clinical trial target

[1]

Disease

[+] 4 Target-related Diseases

Osteoarthritis [ICD-11: FA00-FA05]

Shoulder lesion [ICD-11: FB53]

Soft tissue disorder [ICD-11: FB56]

Alzheimer disease [ICD-11: 8A20]

Function

Responsible for the proteolytic processing of the amyloid precursor protein (app). Cleaves at the amino 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 liquid.

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BioChemical Class

Peptidase

UniProt ID

NOUNIPROTAC

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 16 Clinical Trial Drugs

(S)-FLURBIPROFEN

Drug Info

Preregistration

Myalgia

[2]

E-2609

Drug Info

Phase 3

Alzheimer disease

[3], [4]

verubecestat

Drug Info

Phase 3

Alzheimer disease

[4]

AZD3293

Drug Info

Phase 2/3

Alzheimer disease

[5], [6]

JNJ-54861911

Drug Info

Phase 2/3

Alzheimer disease

[7]

LY2886721

Drug Info

Phase 2

Alzheimer disease

[8], [9]

AZD-3839

Drug Info

Phase 1

Alzheimer disease

[10], [11]

CTS-21166

Drug Info

Phase 1

Alzheimer disease

[12]

HPP-854

Drug Info

Phase 1

Alzheimer disease

[13]

LY-2811376

Drug Info

Phase 1

Alzheimer disease

[14], [15]

RG7129

Drug Info

Phase 1

Alzheimer disease

[16]

AZ-4217

Drug Info

Clinical trial

Rheumatoid arthritis

[17]

oxazine 89

Drug Info

Clinical trial

Diabetic nephropathy

[18]

PMID22911925C2

Drug Info

Clinical trial

Diabetic complication

[19], [20]

PMID23981898C11d

Drug Info

Clinical trial

Cardiovascular disease

[21]

TAK-070

Drug Info

Clinical trial

Solid tumour/cancer

[22]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

SCH-1359113

Drug Info

Preclinical

Alzheimer disease

[23]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

DNP-004089

Drug Info

Terminated

Alzheimer disease

[24]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 47 Inhibitor drugs

(S)-FLURBIPROFEN

Drug Info

[25]

E-2609

Drug Info

[1]

JNJ-54861911

Drug Info

[3], [4]

R-flurbiprofen

Drug Info

[25]

AZD-3839

Drug Info

[29]

CTS-21166

Drug Info

[30]

LY-2811376

Drug Info

[31], [32]

AZ-4217

Drug Info

[17]

oxazine 89

Drug Info

[18]

PMID22911925C2

Drug Info

[20]

PMID23981898C11d

Drug Info

[21]

TAK-070

Drug Info

[22]

SCH-1359113

Drug Info

[33]

DNP-004089

Drug Info

[34]

(-)-CATECHINGALLATE

Drug Info

[35]

(2S)-2'-methoxy kurarinone

Drug Info

[36]

4-(2-aminoethyl)-2-cyclohexylphenol

Drug Info

[37]

4-(2-aminoethyl)-2-ethylphenol

Drug Info

[37]

5,5-Diphenyl-2-iminohydantoin

Drug Info

[38]

6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE

Drug Info

[37]

7-Phloroethol

Drug Info

[39]

AP-2243

Drug Info

[40]

AZ3971

Drug Info

[41]

Bis-7-tacrine

Drug Info

[42]

Carbocyclic Peptidomimetic

Drug Info

[43]

DIECKOL

Drug Info

[39]

Eckol

Drug Info

[39]

example 2 (WO2013004676)

Drug Info

[44]

Glu-Leu-Asp-Leu-(CHOH-CH2)-Ala-Ala-Glu-Phe

Drug Info

[45]

GRL-7234

Drug Info

[46]

GSK-188909

Drug Info

[47]

KMI-172

Drug Info

[48]

KMI-494

Drug Info

[48]

KMI-538

Drug Info

[48]

KMI-596

Drug Info

[49]

KURARINONE

Drug Info

[36]

KUSHENOL A

Drug Info

[36]

LEACHIANONE A

Drug Info

[36]

MMI-175

Drug Info

[50]

N-(1-benzylpiperidin-4-yl)-4-sulfanylbutanamide

Drug Info

[37]

N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINE

Drug Info

[37]

N~3~-BENZYLPYRIDINE-2,3-DIAMINE

Drug Info

[37]

OM00-3

Drug Info

[51]

PHLOROFUCOFUROECKOL A

Drug Info

[39]

PMID21907142CJ

Drug Info

[52]

PMID23412139C16

Drug Info

[53]

TRIPHLOROETHOL A

Drug Info

[39]

Modulator

[+] 5 Modulator drugs

verubecestat

Drug Info

[26]

AZD3293

Drug Info

[27]

LY2886721

Drug Info

[28]

HPP-854

Drug Info

[26]

RG7129

Drug Info

[26]

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 2014 March; 13(3): 319-329.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025057)

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7789).

REF 6

ClinicalTrials.gov (NCT02245737) An Efficacy and Safety Study of AZD3293 in Early Alzheimer's Disease. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT02569398) An Efficacy and Safety Study of JNJ-54861911 in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia.

REF 8

REF 9

Clinical pipeline report, company report or official report of Eli Lilly.

REF 10

REF 11

ClinicalTrials.gov (NCT01348737) Assessment of Safety, Tolerability and Blood Concentrations of Single Doses of AZD3839 in Healthy Volunteers. U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT00621010) Safety Study of CTS21166 to Treat Alzheimer Disease. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT01482013) Safety Study of HPP854 in Subjects With Mild Cognitive Impairment or a Diagnosis of Mild Alzheimer's Disease. U.S. National Institutes of Health.

REF 14

REF 15

ClinicalTrials.gov (NCT00838084) A Safety Study of LY2811376 Single Doses in Healthy Subjects. U.S. National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT01592331) A Pharmacodynamic and Pharmacokinetic Study of RO5508887 in Healthy Volunteers. U.S. National Institutes of Health.

REF 17

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. 2013 Jun 12;33(24):10075-84.

REF 18

beta-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J Med Chem. 2013 May 23;56(10):3980-95.

REF 19

Design and synthesis of potent, orally efficacious hydroxyethylamine derived beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors. J Med Chem. 2012 Nov 8;55(21):9025-44.

REF 20

Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived beta-secretase inhibitors. J Pharmacol Exp Ther. 2012 Nov;343(2):460-7.

REF 21

Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6.

REF 22

A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci. 2010 Aug 18;30(33):11157-66.

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021196)

REF 24

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020178)

REF 25

The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23.

REF 26

BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther. 2014 Dec 24;6(9):89.

REF 27

AZD3293 A novel BACE1 inhibitor: safety, tolerability, and effects on plasma and CSF A-beta peptides following single- and multiple-dose administration. Neurobiology of Aging. May 20, 2008.

REF 28

Lessons from a BACE1 inhibitor trial: off-site but not off base.Alzheimers Dement.2014 Oct;10(5 Suppl):S411-9.

REF 29

Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.

REF 30

ClinicalTrials.gov (NCT00621010) Safety Study of CTS21166 to Treat Alzheimer Disease. U. S. National Institutes of Health. 2008.

REF 31

Neurodegenerative disease: Inhibiting beta-secretase in humans. Nature Reviews Drug Discovery 11, 21 (January 2012).

REF 32

Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16.

REF 33

ACS Meeting News: Using chemistry tools to refine an Alzheimer's drug candidate. C&EN. April 5, 2010. Volume 88, Number 14 p.14.

REF 34

US patent application no. 8,269,019, Inhibitors.

REF 35

Green tea catechins as a BACE1 (beta-secretase) inhibitor. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3905-8.

REF 36

BACE1 inhibitory effects of lavandulyl flavanones from Sophora flavescens. Bioorg Med Chem. 2008 Jul 15;16(14):6669-74.

REF 37

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 38

Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and... J Med Chem. 2010 Feb 11;53(3):951-65.

REF 39

Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3211-5.

REF 40

Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg Med Chem Lett. 2008 Jan 1;18(1):423-6.

REF 41

REF 42

Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. J Med Chem. 2009 Sep 10;52(17):5365-79.

REF 43

Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics. J Med Chem. 2005 Aug 11;48(16):5175-90.

REF 44

Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett. 2013 Mar 15;4(4):379-80.

REF 45

Efficient evaluation of binding free energy using continuum electrostatics solvation. J Med Chem. 2004 Nov 4;47(23):5791-7.

REF 46

Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem. 2007 May 17;50(10):2399-407.

REF 47

Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3664-8.

REF 48

Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1629-33.

REF 49

Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions. Bioorg Med Chem. 2010 May 1;18(9):3175-86.

REF 50

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 51

Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1). Bioorg Med Chem. 2007 Jun 15;15(12):4136-43.

REF 52

Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 2011 Sep 7;14(3):365-77.

REF 53

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS A Reduction. ACS Med Chem Lett. 2012 Nov 8;3(11):897-902.

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