Target Information
Target General Information | Top | |||||
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Target ID |
T45593
(Former ID: TTDI01945)
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Target Name |
Microtubule-associated protein tau (MAPT)
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Synonyms |
tau; Paired helical filamenttau; Paired helical filament-tau; Neurofibrillary tangle protein; MTBT1; MAPTL
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Gene Name |
MAPT
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
2 | Alzheimer disease [ICD-11: 8A20] | |||||
3 | Mild neurocognitive disorder [ICD-11: 6D71] | |||||
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.
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UniProt ID | ||||||
Sequence |
MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG
SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG HVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPA QDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLE FTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPA AAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQK GQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREP KKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLD LSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK LDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDT SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T93LMN |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
1 | LMT-X | Drug Info | Phase 3 | Acute myeloid leukaemia | [3] | |
2 | BIIB092 | Drug Info | Phase 2 | Progressive supranuclear palsy | [8] | |
3 | PBT-2 | Drug Info | Phase 2 | Alzheimer disease | [9] | |
4 | RG6100 | Drug Info | Phase 2 | Alzheimer disease | [10] | |
5 | Tau-binding PET tracer | Drug Info | Phase 2 | Alzheimer disease | [11] | |
6 | LY3303560 | Drug Info | Phase 1 | Alzheimer disease | [16] | |
7 | PTI-80 | Drug Info | Phase 1 | Alzheimer disease | [17] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | LMT-X | Drug Info | [1], [16], [18], [19] | |||
2 | BIIB092 | Drug Info | [19] | |||
3 | RG6100 | Drug Info | [19], [16] | |||
4 | PTI-80 | Drug Info | [21], [1] | |||
Modulator | [+] 5 Modulator drugs | + | ||||
1 | PBT-2 | Drug Info | [20], [1] | |||
2 | Tau-binding PET tracer | Drug Info | [1] | |||
3 | AL-408 | Drug Info | [1] | |||
4 | BLV-0703 | Drug Info | [1] | |||
5 | NI-105 | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
Structure Description | Crystal structure of C-terminal modified Tau peptide-hybrid 4.2f-II with 14-3-3sigma | PDB:6FBW | ||||
Method | X-ray diffraction | Resolution | 1.45 Å | Mutation | No | [22] |
PDB Sequence |
RTPLPG
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: D-Alanine | Ligand Info | |||||
Structure Description | Crystal structure of C-terminal modified Tau peptide-hybrid 3.2d with 14-3-3sigma | PDB:6FI5 | ||||
Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [22] |
PDB Sequence |
TPLP
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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MAPK signaling pathway | hsa04010 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy |
Degree | 24 | Degree centrality | 2.58E-03 | Betweenness centrality | 2.90E-03 |
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Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 5.07E-02 |
Neighborhood connectivity | 2.79E+01 | Topological coefficient | 5.45E-02 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | MAPK signaling pathway | |||||
2 | Alzheimer's disease | |||||
NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
1 | IL2 Signaling Pathway | |||||
2 | EGFR1 Signaling Pathway | |||||
PID Pathway | [+] 2 PID Pathways | + | ||||
1 | LPA receptor mediated events | |||||
2 | Reelin signaling pathway | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | Caspase-mediated cleavage of cytoskeletal proteins | |||||
WikiPathways | [+] 11 WikiPathways | + | ||||
1 | Notch Signaling Pathway | |||||
2 | IL-2 Signaling Pathway | |||||
3 | MAPK Signaling Pathway | |||||
4 | Copper homeostasis | |||||
5 | Kit receptor signaling pathway | |||||
6 | BDNF signaling pathway | |||||
7 | Integrated Pancreatic Cancer Pathway | |||||
8 | Alzheimers Disease | |||||
9 | Regulation of Microtubule Cytoskeleton | |||||
10 | Apoptotic execution phase | |||||
11 | IL-5 Signaling Pathway |
References | Top | |||||
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REF 1 | Microtubules (tau) as an emerging therapeutic target: NAP (davunetide). Curr Pharm Des. 2011;17(31):3413-7. | |||||
REF 2 | ClinicalTrials.gov (NCT01689246) Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease. U.S. National Institutes of Health. | |||||
REF 3 | ClinicalTrials.gov (NCT01689246) Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease. U.S. National Institutes of Health. | |||||
REF 4 | ClinicalTrials.gov (NCT05269394) A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled Platform Trial of Potential Disease Modifying Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints in Dominantly Inherited Alzheimer's Disease. U.S.National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT03828747) A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of MTAU9937A in Patients With Moderate Alzheimer's Disease. U.S.National Institutes of Health. | |||||
REF 6 | ClinicalTrials.gov (NCT04867616) A Patient- and Investigator-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Bepranemab (UCB0107) in Study Participants With Prodromal to Mild Alzheimer's Disease (AD), Followed by an Open-Label Extension Period. U.S.National Institutes of Health. | |||||
REF 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. | |||||
REF 8 | ClinicalTrials.gov (NCT03068468) Study of BIIB092 in Participants With Progressive Supranuclear Palsy (PASSPORT). U.S. National Institutes of Health. | |||||
REF 9 | ClinicalTrials.gov (NCT01590888) Effect of PBT2 in Patients With Early to Mid Stage Huntington Disease. U.S. National Institutes of Health. | |||||
REF 10 | ClinicalTrials.gov (NCT03289143) A Study to Evaluate the Efficacy and Safety of Semorinemab in Patients With Prodromal to Mild Alzheimer's Disease. U.S. National Institutes of Health. | |||||
REF 11 | ClinicalTrials.gov (NCT02414347) F 18 T807 Tau PET Imaging of Alzheimer's Disease. U.S. National Institutes of Health. | |||||
REF 12 | ClinicalTrials.gov (NCT04476303) A Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Phase I Clinical Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of BEY2153 After Oral Administration in Healthy Young and Elderly Male Volunteers. U.S.National Institutes of Health. | |||||
REF 13 | ClinicalTrials.gov (NCT05344989) A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of APNmAb005 in Healthy Subjects. U.S.National Institutes of Health. | |||||
REF 14 | ClinicalTrials.gov (NCT04149860) Interventional, Randomized, Double-blind, Placebo-controlled, Single-ascending-dose Study Investigating the Safety, Tolerability, and Pharmacokinetic Properties of Lu AF87908 in Healthy Subjects and Patients With Alzheimer's Disease. U.S.National Institutes of Health. | |||||
REF 15 | Clinical pipeline report, company report or official report of Prothena | |||||
REF 16 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 17 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028705) | |||||
REF 18 | Clinical pipeline report, company report or official report of TauRx. | |||||
REF 19 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 20 | PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis. 2010;20(2):509-16. | |||||
REF 21 | Biopharmaceutical Research Companies Are Developing More Than 430 Medicines for Top Chronic Diseases Affecting Older Americans. Pharmaceutical Research and Manufacturers of America report. 2014. | |||||
REF 22 | Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. ACS Chem Neurosci. 2018 Nov 21;9(11):2639-2654. |
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