Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTS87KH)

• DTT Name: Microtubule-associated protein tau (MAPT)
• Synonyms: tau; Paired helical filamenttau; Paired helical filament-tau; Neurofibrillary tangle protein; MTBT1; MAPTL
• Gene Name: MAPT
• DTT Type: Clinical trial target; [1]
• UniProt ID: TAU_HUMAN
• TTD ID: T45593
• Sequence:
  MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG
  SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG
  HVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG
  GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPA
  QDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLE
  FTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPA
  AAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS
  DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQK
  GQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREP
  KKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLD
  LSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK
  LDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDT
  SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL
• Function: The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization. Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Alzheimer's disease (hsa05010)
• Reactome Pathway: Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)

Molecular Interaction Atlas (MIA) of This DTT

17 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Davunetide	DMD7K9X	Cognitive impairment	6D71	Phase 3	[1]
LMT-X	DMOFIBM	Acute myeloid leukaemia	2A60	Phase 3	[2]
TRx0237	DM0QNF4	Alzheimer disease	8A20	Phase 3	[3]
E2814	DMZ3Q59	Alzheimer disease	8A20	Phase 2/3	[4]
Bepranemab	DMRQIJO	Alzheimer disease	8A20	Phase 2	[5]
BIIB092	DM263RP	Progressive supranuclear palsy	8A00.10	Phase 2	[6]
JNJ-63733657	DMMKWGJ	Alzheimer disease	8A20	Phase 2	[7]
PBT-2	DMKWGS1	Alzheimer disease	8A20	Phase 2	[8]
RG6100	DMEFD0B	Alzheimer disease	8A20	Phase 2	[6]
Semorinemab	DMA17VD	Alzheimer disease	8A20	Phase 2	[9]
Tau-binding PET tracer	DM9QFW2	Alzheimer disease	8A20	Phase 2	[1]
APNmAb005	DMDVRPZ	Alzheimer disease	8A20	Phase 1	[10]
BEY2153	DMCB2Z0	Alzheimer disease	8A20	Phase 1	[11]
Lu AF87908	DMFSPAT	Alzheimer disease	8A20	Phase 1	[12]
LY3303560	DMG6HLE	Alzheimer disease	8A20	Phase 1	[13]
PRX-005	DMAL2OW	Alzheimer disease	8A20	Phase 1	[14]
PTI-80	DM0A6N9	Alzheimer disease	8A20	Phase 1	[15]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AL-408	DM7K360	Central nervous system disease	8A04-8D87	Investigative	[1]
BLV-0703	DMBRZ4P	Central nervous system disease	8A04-8D87	Investigative	[1]
NI-105	DMPK2JO	Neurodegenerative disorder	8A20-8A23	Investigative	[1]

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	3.76E-06	-0.22	-0.6

References

• [1] Microtubules (tau) as an emerging therapeutic target: NAP (davunetide). Curr Pharm Des. 2011;17(31):3413-7.
• [2] Clinical pipeline report, company report or official report of TauRx.
• [3] Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model. Curr Alzheimer Res. 2020;17(3):285-296.
• [4] Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2020 Feb 4;8(1):13.
• [5] Immunotherapy for Alzheimer's disease: targeting beta-amyloid and beyond. Transl Neurodegener. 2022 Mar 18;11(1):18.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04619420) A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Assess the Efficacy and Safety of JNJ-63733657, an Anti-tau Monoclonal Antibody, in Participants With Early Alzheimer's Disease. U.S.National Institutes of Health.
• [8] PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis. 2010;20(2):509-16.
• [9] Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease. Sci Transl Med. 2021 May 12;13(593):eabb2639.
• [10] Clinical pipeline report, company report or official report of Aprinoia Therapeutics
• [11] Clinical pipeline report, company report or official report of BeyondBio
• [12] Clinical pipeline report, company report or official report of Lundbeck
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] Clinical pipeline report, company report or official report of Prothena
• [15] Biopharmaceutical Research Companies Are Developing More Than 430 Medicines for Top Chronic Diseases Affecting Older Americans. Pharmaceutical Research and Manufacturers of America report. 2014.