Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTE4KHA)

• DTT Name: Amyloid beta A4 protein (APP)
• Synonyms: Protease nexin-II; PreA4; PN-II; Cerebral vascular amyloid peptide; CVAP; Amyloid-beta precursor protein; Amyloid-beta A4 protein; Alzheimer disease amyloid protein; APPI; APP; AD1; ABPP; A4
• Gene Name: APP
• DTT Type: Successful target; [1]
• BioChemical Class: Amyloid beta-protein peptide
• UniProt ID: A4_HUMAN
• TTD ID: T87024
• Sequence:
  MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTK
  TCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVG
  EFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFR
  GVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEE
  EADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPC
  RAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARD
  PVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQA
  KNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITAL
  QAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYER
  MNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTET
  KTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTN
  IKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
  VMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
• Function: Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.
• KEGG Pathway:
  Notch signaling pathway (hsa04330)
  Alzheimer's disease (hsa05010)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Nuclear signaling by ERBB4 (R-HSA-1251985)
• BioCyc Pathway: MetaCyc:ENSG00000142192-MON

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aducanumab	DM51JW4	Alzheimer disease	8A20	Approved	[2]
Florbetapir F-18	DMJ8A3Z	Diagnostic imaging	N.A.	Approved	[1]
GV-971	DMTMA5W	Alzheimer disease	8A20	Approved in China	[3]
Lecanemab	DMW03YD	Alzheimer disease	8A20	Approved	[4]
Nirogacestat	DMUP5Z0	Desmoid tumour	2F7C	Approved	[5]

36 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALZT-OP1	DMG5BTD	Alzheimer disease	8A20	Phase 3	[6]
Bapineuzumab	DMHQ5GK	Alzheimer disease	8A20	Phase 3	[7]
Crenezumab	DM7QI29	Alzheimer disease	8A20	Phase 3	[8]
Curcumin	DMQPH29	Solid tumour/cancer	2A00-2F9Z	Phase 3	[9]
Donanemab	DMPGLIO	Alzheimer disease	8A20	Phase 3	[10]
Gantenerumab	DMWX90U	Alzheimer disease	8A20	Phase 3	[11]
NI-101	DMJ2KIE	Alzheimer disease	8A20	Phase 3	[12]
Solanezumab	DM0HIU5	Alzheimer disease	8A20	Phase 3	[13]
Tramiprosate	DM7BSRH	Alzheimer disease	8A20	Phase 3	[14]
CAD-106	DM31VZT	Alzheimer disease	8A20	Phase 2/3	[15]
ABBV-916	DMGSCJC	Alzheimer disease	8A20	Phase 2	[16]
AD-35	DMVDQO6	Alzheimer disease	8A20	Phase 2	[17]
ALZ-801	DM7ZQAT	Alzheimer disease	8A20	Phase 2	[18]
AN-1792	DM3JNXS	Alzheimer disease	8A20	Phase 2	[19]
FRM-0962	DM9ORUW	Alzheimer disease	8A20	Phase 2	[20]
GSK933776A	DMX27Q1	Alzheimer disease	8A20	Phase 2	[21]
Myo-inositol	DMQKSGI	Alzheimer disease	8A20	Phase 2	[22]
NIC5-15	DMG7XOC	Alzheimer disease	8A20	Phase 2	[23]
Ponezumab	DMIAZ13	Alzheimer disease	8A20	Phase 2	[24]
T-817MA	DMD72F4	Alzheimer disease	8A20	Phase 2	[11]
Trontinemab	DMNCLHJ	Alzheimer disease	8A20	Phase 2	[25]
UB-311	DM4NXWE	Alzheimer disease	8A20	Phase 2	[26]
ACI-24	DM5YDSU	Alzheimer disease	8A20	Phase 1/2	[27]
EB-101	DMH2NKD	Dystrophic epidermolysis bullosa	EC32	Phase 1/2	[8]
11C-6-Me-BTA-1	DMICUPT	Alzheimer disease	8A20	Phase 1	[28]
11C-AZD-2184	DMYVDXW	Alzheimer disease	8A20	Phase 1	[29]
AAB-003/PF-05236812	DM92RQT	Alzheimer disease	8A20	Phase 1	[8]
ACU193	DM5BISI	Alzheimer disease	8A20	Phase 1	[30]
Affitope AD-01	DM0I8RZ	Alzheimer disease	8A20	Phase 1	[31]
Anti-N3pG-Abeta antibody	DMRWI7E	Alzheimer disease	8A20	Phase 1	[32]
ANVS301	DMHT1AS	Alzheimer disease	8A20	Phase 1	[33]
BEY2153	DMCB2Z0	Alzheimer disease	8A20	Phase 1	[34]
DWP-09031	DM4XZY9	Alzheimer disease	8A20	Phase 1	[8]
LY3372993	DMACGI7	Alzheimer disease	8A20	Phase 1	[35]
SAR228810	DMTFAGU	Alzheimer disease	8A20	Phase 1	[36]
Systebryl	DMD23AX	Amyloidosis	5D00	Phase 1	[8]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Affitope AD-02	DMSF5VK	Alzheimer disease	8A20	Discontinued in Phase 2	[37]
RN6G	DM5P1KQ	Age-related macular degeneration	9B75.0	Discontinued in Phase 2	[38]
PF-05236812	DM68PYA	Alzheimer disease	8A20	Discontinued in Phase 1	[2]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AAB-002	DMC7EQT	Alzheimer disease	8A20	Phase 0	[8]
NN-818	DMLNYGX	Brain injury	NA07.Z	Preclinical	[8]
Pepticlere	DMA5T3J	Alzheimer disease	8A20	Preclinical	[39]

66 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,6-bis(4'-aminophenyl)-hexa-1,3,5-triene	DM70ODN	Discovery agent	N.A.	Investigative	[40]
1,6-bis(4'-dimethylaminophenyl)-hexa-1,3,5-triene	DMBCU6W	Discovery agent	N.A.	Investigative	[40]
1,6-Bis(4'-hydroxyphenyl)-hexa-1,3,5-triene	DMEU3MN	Discovery agent	N.A.	Investigative	[40]
1,6-bis(4'-methylaminophenyl)-hexa-1,3,5-triene	DM0D6JN	Discovery agent	N.A.	Investigative	[40]
1,6-bis(4'-nitrophenyl)-hexa-1,3,5-triene	DMQY75B	Discovery agent	N.A.	Investigative	[40]
11A1	DMFVP6K	Alzheimer disease	8A20	Investigative	[8]
123I-DRM-106	DMW172Q	Alzheimer disease	8A20	Investigative	[8]
18F-AV-45 dimer	DMAPI2G	Cerebral amyloid angiopathy	5D00.0	Investigative	[8]
2,5-bis(2-methoxyphenyl)thiophene	DMU5GKN	Discovery agent	N.A.	Investigative	[41]
2,5-bis(4-Hydroxyphenyl)thiophene	DMNQIGZ	Discovery agent	N.A.	Investigative	[41]
2,5-bis(4-methoxyphenyl)thiophene	DM30RNY	Discovery agent	N.A.	Investigative	[41]
2,5-bis(4-nitrophenyl)thiophene	DM3USOR	Discovery agent	N.A.	Investigative	[41]
2-(4-(methylamino)phenyl)benzo[d]thiazol-6-ol	DMFNQZS	Discovery agent	N.A.	Investigative	[40]
2-(4-nitrophenyl)-5-(4-methoxyphenyl)thiophene	DMX8U32	Discovery agent	N.A.	Investigative	[41]
4-(5-(4-(methylamino)phenyl)thiophen-2-yl)phenol	DMGHVW7	Discovery agent	N.A.	Investigative	[41]
4-(5-(4-aminophenyl)thiophen-2-yl)benzenamine	DMOGMJ9	Discovery agent	N.A.	Investigative	[41]
4-(5-(4-aminophenyl)thiophen-2-yl)phenol	DM1UX89	Discovery agent	N.A.	Investigative	[41]
4-(5-(4-methoxyphenyl)thiophen-2-yl)benzenamine	DMO9YH0	Discovery agent	N.A.	Investigative	[41]
4-(5-(4-methoxyphenyl)thiophen-2-yl)phenol	DMCNLBZ	Discovery agent	N.A.	Investigative	[41]
5-hydroxy-2-(4-aminophenyl)benzofuran	DM8KON3	Discovery agent	N.A.	Investigative	[42]
5-hydroxy-2-(4-dimethylaminophenyl)benzofuran	DMYL0ZF	Discovery agent	N.A.	Investigative	[42]
5-hydroxy-2-(4-methylaminophenyl)benzofuran	DM4QC0R	Discovery agent	N.A.	Investigative	[42]
5-methoxy-2-(4-aminophenyl)benzofuran	DMW7IXL	Discovery agent	N.A.	Investigative	[42]
5-methoxy-2-(4-dimethylaminophenyl)benzofuran	DM3NUMG	Discovery agent	N.A.	Investigative	[42]
5-methoxy-2-(4-methylaminophenyl)benzofuran	DM5N1JX	Discovery agent	N.A.	Investigative	[42]
6-iodo-4'-dimethyaminoflavone	DMAL1UH	Discovery agent	N.A.	Investigative	[43]
6-iodo-4'-hydroxyflavone	DM5FZBI	Discovery agent	N.A.	Investigative	[43]
6-iodo-4'-methoxyflavone	DM6U9CY	Discovery agent	N.A.	Investigative	[43]
6-iodo-4'-methylaminoflavone	DM9GJAY	Discovery agent	N.A.	Investigative	[43]
A-887755	DM8IWUE	Alzheimer disease	8A20	Investigative	[8]
Abloid	DMKN10X	Alzheimer disease	8A20	Investigative	[8]
ACI-636	DMPLNTM	Alzheimer disease	8A20	Investigative	[8]
ACU-0101979	DM7ZWRN	Alzheimer disease	8A20	Investigative	[8]
AD-0802	DM23QND	Alzheimer disease	8A20	Investigative	[8]
ANA-5	DM3DPSO	Alzheimer disease	8A20	Investigative	[8]
Anticalin	DMQJ3ZL	Alzheimer disease	8A20	Investigative	[8]
ARC-069	DMSM1PV	Alzheimer disease	8A20	Investigative	[8]
ARN-2966	DMBE0H8	Alzheimer disease	8A20	Investigative	[8]
AS-602704	DMANU3W	Discovery agent	N.A.	Investigative	[44]
AZ4800	DMATC5P	Discovery agent	N.A.	Investigative	[45]
BAN-2203	DMX6KTO	Alzheimer disease	8A20	Investigative	[8]
CD45RB	DMFQVLW	Glioma	2A00.0	Investigative	[8]
Chrysamine -G	DMLEXN0	Discovery agent	N.A.	Investigative	[9]
CT-003230	DM3W6PQ	Cognitive impairment	6D71	Investigative	[8]
DBT-1339	DM09YI7	Alzheimer disease	8A20	Investigative	[8]
DEHYDROZINGERONE	DM9TWR7	Discovery agent	N.A.	Investigative	[9]
EDN-OL1	DMHCGIS	Alzheimer disease	8A20	Investigative	[8]
ELND-007	DM5G1SF	Alzheimer disease	8A20	Investigative	[46]
Gamma-secretase modulators	DMG7UPR	Alzheimer disease	8A20	Investigative	[8]
Gelsolin	DML0OUY	Discovery agent	N.A.	Investigative	[47]
IN-N01	DMI5N23	Brain injury	NA07.Z	Investigative	[8]
KMS-88009	DM2K81B	Alzheimer disease	8A20	Investigative	[8]
KNX-Monoclonal204	DMNWXCA	Alzheimer disease	8A20	Investigative	[8]
Methionine Sulfoxide	DMKE18W	Discovery agent	N.A.	Investigative	[48]
Mimovax	DM7DT20	Alzheimer disease	8A20	Investigative	[8]
PA-1637	DMUH203	Neurological disorder	6B60	Investigative	[8]
RECALL-VAX	DM1XFE9	Alzheimer disease	8A20	Investigative	[8]
SB-13	DM9O0AR	Discovery agent	N.A.	Investigative	[40]
SEM-606	DMDIZUT	Neurological disorder	6B60	Investigative	[8]
SEN-1500	DMKB2IJ	Alzheimer disease	8A20	Investigative	[8]
SP-08	DM2TRIZ	Alzheimer disease	8A20	Investigative	[8]
SR-973	DMU48OD	Discovery agent	N.A.	Investigative	[49]
TKP-1001	DMDBUXR	Alzheimer disease	8A20	Investigative	[8]
Turmeric extracts	DM3QE8P	Alzheimer disease	8A20	Investigative	[8]
VK-11	DM7FQD0	Alzheimer disease	8A20	Investigative	[8]
VK-12	DMRQBEW	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	1.60E-02	-0.07	-0.31
Breast cancer	2C82	Breast tissue	4.56E-07	0.34	0.44
Glioma	2C82	Brainstem tissue	7.29E-01	-0.07	-0.13
Glioma	2C82	White matter	1.34E-04	-0.51	-1.73
Parkinson's disease	8A00.0	Substantia nigra tissue	2.13E-01	-0.03	-0.06

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