Target Information
| Target General Information | Top | |||||
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| Target ID |
T17852
(Former ID: TTDI02148)
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| Target Name |
Phosphodiesterase 9 (PDE9)
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| Synonyms |
High affinity cGMPspecific 3',5'cyclic phosphodiesterase 9A; High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
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| Gene Name |
PDE9A
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 8 Target-related Diseases | + | ||||
| 1 | Dementia [ICD-11: 6D80-6D8Z] | |||||
| 2 | Genitourinary disease [ICD-11: GA0Z-GC8Z] | |||||
| 3 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| 4 | Mental/behavioural/neurodevelopmental disorder [ICD-11: 6E20-6E8Z] | |||||
| 5 | Parkinsonism [ICD-11: 8A00] | |||||
| 6 | Schizophrenia [ICD-11: 6A20] | |||||
| 7 | Sickle-cell disorder [ICD-11: 3A51] | |||||
| 8 | Alzheimer disease [ICD-11: 8A20] | |||||
| Function |
Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP. Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart. Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein. In brain, involved in cognitive function, such as learning and long-term memory. Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.35
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| Sequence |
MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAM
VSIDPTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRRE GAFESGQVEPRPREPQGCYQEGQRIPPEREELIQSVLAQVAEQFSRAFKINELKAEVANH LAVLEKRVELEGLKVVEIEKCKSDIKKMREELAARSSRTNCPCKYSFLDNHKKLTPRRDV PTYPKYLLSPETIEALRKPTFDVWLWEPNEMLSCLEHMYHDLGLVRDFSINPVTLRRWLF CVHDNYRNNPFHNFRHCFCVAQMMYSMVWLCSLQEKFSQTDILILMTAAICHDLDHPGYN NTYQINARTELAVRYNDISPLENHHCAVAFQILAEPECNIFSNIPPDGFKQIRQGMITLI LATDMARHAEIMDSFKEKMENFDYSNEEHMTLLKMILIKCCDISNEVRPMEVAEPWVDCL LEEYFMQSDREKSEGLPVAPFMDRDKVTKATAQIGFIKFVLIPMFETVTKLFPMVEEIML QPLWESRDRYEELKRIDDAMKELQKKTDSLTSGATEKSRERSRDVKNSEGDCA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | ASP-4901 | Drug Info | Phase 2 | Genitourinary disease | [5] | |
| 2 | E2027 | Drug Info | Phase 2 | Parkinson disease | [6] | |
| 3 | PF-4447943 | Drug Info | Phase 2 | Alzheimer disease | [7] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | ASP-4901 | Drug Info | [9] | |||
| 2 | PF-4447943 | Drug Info | [1] | |||
| 3 | PF-4181366 | Drug Info | [12] | |||
| 4 | SCH51866 | Drug Info | [13] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | E2027 | Drug Info | [10], [11] | |||
| 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: PF-4447943 | Ligand Info | |||||
| Structure Description | Human phosphodiesterase 9 in complex with inhibitors | PDB:4E90 | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [14] |
| PDB Sequence |
GSHMTYPKYL
187 LSPETIEALR197 KPTFDVWLWE207 PNEMLSCLEH217 MYHDLGLVRD227 FSINPVTLRR 237 WLFCVHDNYR247 NNPFHNFRHC257 FCVAQMMYSM267 VWLCSLQEKF277 SQTDILILMT 287 AAICHDLDHP297 GYNNTYQINA307 RTELAVRYND317 ISPLENHHCA327 VAFQILAEPE 337 CNIFSNIPPD347 GFKQIRQGMI357 TLILATDMAR367 HAEIMDSFKE377 KMENFDYSNE 387 EHMTLLKMIL397 IKCCDISNEV407 RPMEVAEPWV417 DCLLEEYFMQ427 SDREKSEGLP 437 VAPFMDRDKV447 TKATAQIGFI457 KFVLIPMFET467 VTKLFPMVEE477 IMLQPLWESR 487 DRYEELKRID497 DAMKELQK
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| Ligand Name: Cyclic Guanosine Monophosphate | Ligand Info | |||||
| Structure Description | human phosphodiestrase 9 in complex with cGMP (Zn inhibited) | PDB:3DYN | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [15] |
| PDB Sequence |
GSHMTYPKYL
187 LSPETIEALR197 KPTFDVWLWE207 PNEMLSCLEH217 MYHDLGLVRD227 FSINPVTLRR 237 WLFCVHDNYR247 NNPFHNFRHC257 FCVAQMMYSM267 VWLCSLQEKF277 SQTDILILMT 287 AAICHDLDHP297 GYNNTYQINA307 RTELAVRYND317 ISPLENHHCA327 VAFQILAEPE 337 CNIFSNIPPD347 GFKQIRQGMI357 TLILATDMAR367 HAEIMDSFKE377 KMENFDYSNE 387 EHMTLLKMIL397 IKCCDISNEV407 RPMEVAEPWV417 DCLLEEYFMQ427 SDREKSEGLP 437 VAPFMDRDKV447 TKATAQIGFI457 KFVLIPMFET467 VTKLFPMVEE477 IMLQPLWESR 487 DRYEELKRID497 DAMKELQK
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 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 Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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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 | ||
| 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 | [+] 1 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Regulation of Androgen receptor activity | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | cGMP effects | |||||
| References | Top | |||||
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| REF 1 | A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer's disease. Curr Alzheimer Res. 2014;11(5):413-21. | |||||
| REF 2 | ClinicalTrials.gov (NCT02240693) Alzheimer Disease Proof of Concept Study With BI 409306 Versus Placebo. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03401112) A Study of IMR-687 in Adult Patients With Sickle Cell Anaemia (Homozygous HbSS or Sickle-beta0 Thalassemia). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT05409183) A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess the Effectiveness of CRD-740 in Subjects With Chronic Heart Failure (CARDINAL-HF). U.S.National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT02038868) A Study to Evaluate the Efficacy and Safety of ASP4901 in Patients With Benign Prostate Hyperplasia. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT04764669) A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT00930059) A Study Of PF-04447943 Compared To Placebo In Subjects With Mild To Moderate Alzheimer's Disease. U.S. National Institutes of Health. | |||||
| REF 8 | Clinical pipeline report, company report or official report of TransThera Biosciences | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033070) | |||||
| REF 10 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | 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: 1309). | |||||
| REF 13 | Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem. 1998 Jun 19;273(25):15559-64. | |||||
| REF 14 | Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors. J Med Chem. 2012 Nov 8;55(21):9055-68. | |||||
| REF 15 | Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13309-14. | |||||
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