Target Information
| Target General Information | Top | |||||
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| Target ID |
T84133
(Former ID: TTDNC00456)
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| Target Name |
Phosphodiesterase 10A (PDE10)
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| Synonyms |
cAMP and cAMPinhibited cGMP 3',5'cyclic phosphodiesterase 10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Click to Show/Hide
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| Gene Name |
PDE10A
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Choreiform disorder [ICD-11: 8A01] | |||||
| 2 | Inborn purine/pyrimidine/nucleotide metabolism error [ICD-11: 5C55] | |||||
| 3 | Irritable bowel syndrome [ICD-11: DD91] | |||||
| 4 | Schizophrenia [ICD-11: 6A20] | |||||
| 5 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. May play a critical role in regulating cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition. Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides.
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.17
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| Sequence |
MRIEERKSQHLTGLTDEKVKAYLSLHPQVLDEFVSESVSAETVEKWLKRKNNKSEDESAP
KEVSRYQDTNMQGVVYELNSYIEQRLDTGGDNQLLLYELSSIIKIATKADGFALYFLGEC NNSLCIFTPPGIKEGKPRLIPAGPITQGTTVSAYVAKSRKTLLVEDILGDERFPRGTGLE SGTRIQSVLCLPIVTAIGDLIGILELYRHWGKEAFCLSHQEVATANLAWASVAIHQVQVC RGLAKQTELNDFLLDVSKTYFDNIVAIDSLLEHIMIYAKNLVNADRCALFQVDHKNKELY SDLFDIGEEKEGKPVFKKTKEIRFSIEKGIAGQVARTGEVLNIPDAYADPRFNREVDLYT GYTTRNILCMPIVSRGSVIGVVQMVNKISGSAFSKTDENNFKMFAVFCALALHCANMYHR IRHSECIYRVTMEKLSYHSICTSEEWQGLMQFTLPVRLCKEIELFHFDIGPFENMWPGIF VYMVHRSCGTSCFELEKLCRFIMSVKKNYRRVPYHNWKHAVTVAHCMYAILQNNHTLFTD LERKGLLIACLCHDLDHRGFSNSYLQKFDHPLAALYSTSTMEQHHFSQTVSILQLEGHNI FSTLSSSEYEQVLEIIRKAIIATDLALYFGNRKQLEEMYQTGSLNLNNQSHRDRVIGLMM TACDLCSVTKLWPVTKLTANDIYAEFWAEGDEMKKLGIQPIPMMDRDKKDEVPQGQLGFY NAVAIPCYTTLTQILPPTEPLLKACRDNLSQWEKVIRGEETATWISSPSVAQKAAASED Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T38G6P | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 9 Clinical Trial Drugs | + | ||||
| 1 | Lu AF11167 | Drug Info | Phase 2 | Schizophrenia | [2] | |
| 2 | OMS824 | Drug Info | Phase 2 | Huntington disease | [3] | |
| 3 | PF-02545920 | Drug Info | Phase 2 | Schizophrenia | [4] | |
| 4 | TAK-063 | Drug Info | Phase 2 | Schizophrenia | [5] | |
| 5 | Tofisopam | Drug Info | Phase 2 | Irritable bowel syndrome | [6] | |
| 6 | FRM-6308 | Drug Info | Phase 1b | Schizophrenia | [7] | |
| 7 | AMG 579 | Drug Info | Phase 1 | Schizophrenia | [8] | |
| 8 | PBF-999 | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
| 9 | RG7203 | Drug Info | Phase 1 | Schizophrenia | [10] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 40 Inhibitor drugs | + | ||||
| 1 | Lu AF11167 | Drug Info | [11] | |||
| 2 | OMS824 | Drug Info | [1] | |||
| 3 | PF-02545920 | Drug Info | [12] | |||
| 4 | TAK-063 | Drug Info | [13] | |||
| 5 | Tofisopam | Drug Info | [14] | |||
| 6 | FRM-6308 | Drug Info | [15] | |||
| 7 | AMG 579 | Drug Info | [16] | |||
| 8 | PBF-999 | Drug Info | [17] | |||
| 9 | RG7203 | Drug Info | [18] | |||
| 10 | 1,2,4-triazole [4,3-a]quinoxaline derivative 1 | Drug Info | [19] | |||
| 11 | 1,2,4-triazole [4,3-a]quinoxaline derivative 2 | Drug Info | [19] | |||
| 12 | 1,2,4-triazole [4,3-a]quinoxaline derivative 3 | Drug Info | [19] | |||
| 13 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 3 | Drug Info | [19] | |||
| 14 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 4 | Drug Info | [19] | |||
| 15 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 5 | Drug Info | [19] | |||
| 16 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 6 | Drug Info | [19] | |||
| 17 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 1 | Drug Info | [19] | |||
| 18 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 2 | Drug Info | [19] | |||
| 19 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 3 | Drug Info | [19] | |||
| 20 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 4 | Drug Info | [19] | |||
| 21 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 5 | Drug Info | [19] | |||
| 22 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 6 | Drug Info | [19] | |||
| 23 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 7 | Drug Info | [19] | |||
| 24 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 8 | Drug Info | [19] | |||
| 25 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 1 | Drug Info | [19] | |||
| 26 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 2 | Drug Info | [19] | |||
| 27 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 3 | Drug Info | [19] | |||
| 28 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 4 | Drug Info | [19] | |||
| 29 | PMID27321640-Compound-58 | Drug Info | [19] | |||
| 30 | PMID27321640-Compound-59 | Drug Info | [19] | |||
| 31 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 1 | Drug Info | [19] | |||
| 32 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 2 | Drug Info | [19] | |||
| 33 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 3 | Drug Info | [19] | |||
| 34 | Pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine derivative 1 | Drug Info | [19] | |||
| 35 | Pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine derivative 2 | Drug Info | [19] | |||
| 36 | Triazolo-pyridine derivative 2 | Drug Info | [19] | |||
| 37 | Triazolo-pyridine derivative 3 | Drug Info | [19] | |||
| 38 | Triazolo-pyridine derivative 4 | Drug Info | [19] | |||
| 39 | Triazolo-pyridine derivative 5 | Drug Info | [19] | |||
| 40 | Triazolo-pyridine derivative 6 | Drug Info | [19] | |||
| 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: Papaverine | Ligand Info | |||||
| Structure Description | Human PDE-papaverine complex obtained by ligand soaking of cross- linked protein crystals | PDB:2WEY | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [20] |
| PDB Sequence |
HMSICTSEEW
456 QGLMQFTLPV466 RLCKEIELFH476 FDIGPFENMW486 PGIFVYMVHR496 SCGTSCFELE 506 KLCRFIMSVK516 KNYRRVPYHN526 WKHAVTVAHC536 MYAILQNNHT546 LFTDLERKGL 556 LIACLCHDLD566 HRGFSNSYLQ576 KFDHPLAALY586 STSTMEQHHF596 SQTVSILQLE 606 GHNIFSTLSS616 SEYEQVLEII626 RKAIIATDLA636 LYFGNRKQLE646 EMYQTGSLNL 656 NNQSHRDRVI666 GLMMTACDLC676 SVTKLWPVTK686 LTANDIYAEF696 WAEGDEMKKL 706 GIQPIPMMDR716 DKKDEVPQGQ726 LGFYNAVAIP736 CYTTLTQILP746 PTEPLLKACR 756 DNLSQWEKVI766 RGEE
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| Ligand Name: Adenosine monophosphate | Ligand Info | |||||
| Structure Description | crystal structure of PDE10A2 in complex with AMP | PDB:2OUN | ||||
| Method | X-ray diffraction | Resolution | 1.56 Å | Mutation | No | [21] |
| PDB Sequence |
HMSICTSEEW
456 QGLMQFTLPV466 RLCKEIELFH476 FDIGPFENMW486 PGIFVYMVHR496 SCGTSCFELE 506 KLCRFIMSVK516 KNYRRVPYHN526 WKHAVTVAHC536 MYAILQNNHT546 LFTDLERKGL 556 LIACLCHDLD566 HRGFSNSYLQ576 KFDHPLAALY586 STSTMEQHHF596 SQTVSILQLE 606 GHNIFSTLSS616 SEYEQVLEII626 RKAIIATDLA636 LYFGNRKQLE646 EMYQTGSLNL 656 NNQSHRDRVI666 GLMMTACDLC676 SVTKLWPVTK686 LTANDIYAEF696 WAEGDEMKKL 706 GIQPIPMMDR716 DKKDEVPQGQ726 LGFYNAVAIP736 CYTTLTQILP746 PTEPLLKACR 756 DNLSQWEKVI766 RGEE
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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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| 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 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 | Purine metabolism | |||||
| 2 | Morphine addiction | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Purine Metabolism | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | cGMP effects | |||||
| 2 | G alpha (s) signalling events | |||||
| References | Top | |||||
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| REF 1 | New Drugs/Drug News. P T. 2013 November; 38(11): 667-672. | |||||
| REF 2 | ClinicalTrials.gov (NCT03929497) Flexible-dose Long-term Extension Study of Lu AF11167 in Patients With Schizophrenia With Prominent Negative Symptoms. U.S. National Institutes of Health. | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025042) | |||||
| REF 4 | ClinicalTrials.gov (NCT01939548) An Outpatient Study Of The Efficacy, Safety, And Tolerability Of PF-02545920 In The Adjunctive Treatment Of Sub-Optimally Controlled Symptoms of Schizophrenia. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT02477020) A Phase 2 Efficacy and Safety Study of TAK-063 in Participants With an Acute Exacerbation of Schizophrenia. | |||||
| REF 6 | ClinicalTrials.gov (NCT00486876) A Study of 3 Doses of Dextofisopam in Females With Irritable Bowel Syndrome. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of Forum pharmaceuticals. | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035904) | |||||
| REF 9 | ClinicalTrials.gov (NCT03786484) Study of PBF-999 in Solid Tumour Advanced Cancer. U.S. National Institutes of Health. | |||||
| REF 10 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 11 | PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?. Front Neurosci. 2021 Jan 20;14:600178. | |||||
| REF 12 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 13 | Characterization of Binding and Inhibitory Properties of TAK-063, a Novel Phosphodiesterase 10A Inhibitor. PLoS One. 2015; 10(3): e0122197. | |||||
| REF 14 | The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. | |||||
| REF 15 | Massive schizophrenia genomics study offers new drug directions. Nat Rev Drug Discov. 2014 Sep;13(9):641-2. | |||||
| REF 16 | Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase10A (PDE10A). J Med Chem. 2014 Aug 14;57(15):6632-41. | |||||
| REF 17 | Clinical pipeline report, company report or official report of Palobiofarma. | |||||
| REF 18 | Synaptic synopsis. SciBX 6(41); doi:10.1038/scibx.2013.1153. Oct. 24, 2013 | |||||
| REF 19 | Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2016 Aug;26(8):933-46. | |||||
| REF 20 | Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure. Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):872-4. | |||||
| REF 21 | Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. | |||||
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