Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT8JRS7)

• DTT Name: Beta-secretase (BACE)
• Synonyms: Transmembrane aspartic protease; Beta-site amyloid precursor protein cleaving enzyme; Beta-site AbetaPP-cleaving enzyme; BACE1
• Gene Name: BACE
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: NOUNIPROTAC
• TTD ID: T73992
• 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.

Molecular Interaction Atlas (MIA) of This DTT

19 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-FLURBIPROFEN	DMF2O4T	Myalgia	FB56.2	Preregistration	[2]
E-2609	DMTNUJ8	Alzheimer disease	8A20	Phase 3	[1]
Lanabecestat	DMFJLB6	Alzheimer disease	8A20	Phase 3	[3]
verubecestat	DM4CGH5	Alzheimer disease	8A20	Phase 3	[4]
AZD3293	DMJQHXD	Alzheimer disease	8A20	Phase 2/3	[5]
JNJ-54861911	DMGPJ5U	Alzheimer disease	8A20	Phase 2/3	[3]
LY2886721	DMV14LM	Alzheimer disease	8A20	Phase 2	[6]
LY3202626	DM7IFNB	Alzheimer disease	8A20	Phase 2	[3]
R-flurbiprofen	DMFIVSR	N. A.	N. A.	Phase 2	[2]
AZD-3839	DM72FOD	Alzheimer disease	8A20	Phase 1	[7]
CTS-21166	DM68I93	Alzheimer disease	8A20	Phase 1	[8]
HPP-854	DMSLDHG	Alzheimer disease	8A20	Phase 1	[4]
LY-2811376	DM8LGWR	Alzheimer disease	8A20	Phase 1	[9]
RG7129	DMTWSM2	Alzheimer disease	8A20	Phase 1	[4]
AZ-4217	DMGPTFL	Rheumatoid arthritis	FA20	Clinical trial	[10]
oxazine 89	DMXFI90	Diabetic nephropathy	GB61.Z	Clinical trial	[11]
PMID22911925C2	DM5UWH3	Diabetic complication	5A2Y	Clinical trial	[12]
PMID23981898C11d	DMX1IZ9	Cardiovascular disease	BA00-BE2Z	Clinical trial	[13]
TAK-070	DMCM5GK	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[14]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SCH-1359113	DMLG682	Alzheimer disease	8A20	Preclinical	[15]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DNP-004089	DMXR3V1	Alzheimer disease	8A20	Terminated	[16]

35 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-CATECHINGALLATE	DMZOGSK	Discovery agent	N.A.	Investigative	[17]
(2S)-2'-methoxy kurarinone	DMZOX43	Discovery agent	N.A.	Investigative	[18]
4-(2-aminoethyl)-2-cyclohexylphenol	DMZSN1Y	Discovery agent	N.A.	Investigative	[19]
4-(2-aminoethyl)-2-ethylphenol	DMF8D5S	Discovery agent	N.A.	Investigative	[19]
4-(4-FLUOROBENZYL)PIPERIDINE	DMW8IN3	Discovery agent	N.A.	Investigative	[19]
5,5-Diphenyl-2-iminohydantoin	DM28LNV	Discovery agent	N.A.	Investigative	[20]
6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE	DMNJPCD	Discovery agent	N.A.	Investigative	[19]
7-Phloroethol	DM19I62	Discovery agent	N.A.	Investigative	[21]
AP-2243	DMRYL9X	Discovery agent	N.A.	Investigative	[22]
AZ3971	DMVMW9S	Discovery agent	N.A.	Investigative	[23]
Bis-7-tacrine	DMVNC1R	Discovery agent	N.A.	Investigative	[24]
Carbocyclic Peptidomimetic	DM87SOX	Discovery agent	N.A.	Investigative	[25]
DIECKOL	DMBCK4G	Discovery agent	N.A.	Investigative	[21]
DIOXINODEHYDROECKOL	DML2B04	Discovery agent	N.A.	Investigative	[21]
Eckol	DMIVY0Q	Discovery agent	N.A.	Investigative	[21]
example 2 (WO2013004676)	DMU25HZ	Discovery agent	N.A.	Investigative	[26]
Glu-Leu-Asp-Leu-(CHOH-CH2)-Ala-Ala-Glu-Phe	DMXBQRJ	Discovery agent	N.A.	Investigative	[27]
GRL-7234	DMR93MK	Discovery agent	N.A.	Investigative	[28]
GSK-188909	DMMWBU6	Discovery agent	N.A.	Investigative	[29]
KMI-172	DMLRVEJ	Discovery agent	N.A.	Investigative	[30]
KMI-494	DMQ4WNB	Discovery agent	N.A.	Investigative	[30]
KMI-538	DMX9EA7	Discovery agent	N.A.	Investigative	[30]
KMI-596	DMXUETW	Discovery agent	N.A.	Investigative	[31]
KURARINONE	DMH0G8W	Discovery agent	N.A.	Investigative	[18]
KUSHENOL A	DMCFHPD	Discovery agent	N.A.	Investigative	[18]
LEACHIANONE A	DMZ21HU	Discovery agent	N.A.	Investigative	[18]
MMI-175	DMH1YN6	Discovery agent	N.A.	Investigative	[32]
N-(1-benzylpiperidin-4-yl)-4-sulfanylbutanamide	DMEKSHG	Discovery agent	N.A.	Investigative	[19]
N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINE	DML35GB	Discovery agent	N.A.	Investigative	[19]
N~3~-BENZYLPYRIDINE-2,3-DIAMINE	DMOCQ9I	Discovery agent	N.A.	Investigative	[19]
OM00-3	DMXJ2SM	Discovery agent	N.A.	Investigative	[33]
PHLOROFUCOFUROECKOL A	DMO1I6G	Discovery agent	N.A.	Investigative	[21]
PMID21907142CJ	DMST0IN	Discovery agent	N.A.	Investigative	[34]
PMID23412139C16	DM9O8I7	Discovery agent	N.A.	Investigative	[35]
TRIPHLOROETHOL A	DMF8QR6	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	6.98E-04	1.03	2.84

References

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• [2] 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.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther. 2014 Dec 24;6(9):89.
• [5] 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.
• [6] Lessons from a BACE1 inhibitor trial: off-site but not off base.Alzheimers Dement.2014 Oct;10(5 Suppl):S411-9.
• [7] 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.
• [8] ClinicalTrials.gov (NCT00621010) Safety Study of CTS21166 to Treat Alzheimer Disease. U. S. National Institutes of Health. 2008.
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• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] ACS Meeting News: Using chemistry tools to refine an Alzheimer's drug candidate. C&EN. April 5, 2010. Volume 88, Number 14 p.14.
• [16] US patent application no. 8,269,019, Inhibitors.
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• [23] 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. (Target id: 2330).
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• [25] 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.
• [26] Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett. 2013 Mar 15;4(4):379-80.
• [27] Efficient evaluation of binding free energy using continuum electrostatics solvation. J Med Chem. 2004 Nov 4;47(23):5791-7.
• [28] 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.
• [29] Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3664-8.
• [30] 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.
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