Molecular And Cellular Understanding of PDE10A: A Dual‐Substrate Phosphodiesterase with Therapeutic Potential to Modulate Basal Ganglia Function

Charych, Erik I.; Brandon, Nicholas J.

doi:10.1002/9781118836507.ch10

Cited by 5 publications

(5 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To verify the 90 kDa band as PDE10A, we incubated striatal membranes with PF-942 (30 nM) and after UV crosslinking, conjugated a biotinylated TAMRA fluorophore (Biotin-TAMRA-N 3 ) to the probe-labeled protein(s). This approach allowed us to [5] enrich for proteins which were labeled with the photoprobe using streptavidin (SA) magnetic beads.…”

Section: Resultsmentioning

confidence: 99%

“…4 PDE10A is highly enriched in medium spiny neurons of the striatum and is therefore well-positioned to regulate basal ganglia circuitry which is central to neurological diseases like Parkinson's disease, Huntington's disease, Tourette syndrome, addiction and schizophrenia. [5][6][7] PDE10A inhibition has been shown to regulate cyclic nucleotide signaling pathways in the striatum and be efficacious in preclinical models for assessing antipsychotic drug action and reversing behavioral cellular phenotypes in Huntington's disease models. [8][9][10] Besides its impact on brain pathways, PDE10A has also been shown to be involved in the regulation of proliferative states in pulmonary hypertension and colon cancer.…”

mentioning

confidence: 99%

“…PDEs are believed to be excellent drug targets based on their role in regulating key intracellular processes and the demonstrated ability to develop small molecule inhibitors of these enzymes. − This very diverse class of proteins consists of 11 different families (PDE1 to PDE11), classified based on sequence homology, substrate specificity, and domain architecture, with multiple different isoforms derived from separate genes or splice variants . PDE10A is highly enriched in medium spiny neurons of the striatum and is therefore well-positioned to regulate basal ganglia circuitry, which is central to neurological diseases like Parkinson’s disease, Huntington’s disease, Tourette syndrome, addiction, and schizophrenia. − PDE10A inhibition has been shown to regulate cyclic nucleotide signaling pathways in the striatum and be efficacious in preclinical models for assessing antipsychotic drug action and reversing behavioral cellular phenotypes in Huntington’s disease models. − Besides its impact on brain pathways, PDE10A has also been shown to be involved in the regulation of proliferative states in pulmonary hypertension and colon cancer. , Therefore, PDE10A inhibitors are promising pharmaceuticals, and demonstration of their efficacy to ameliorate disease symptoms is actively being pursued by several drug companies . Pfizer’s PDE10A inhibitor MP-10 (PF-2545920) was found to be ineffective in a 4-week monotherapy trial investigating the effect of the drug on the acute exacerbation of psychosis in patients suffering from schizophrenia but is still in clinical testing for adjunctive therapy in schizophrenia and Huntington’s disease (: NCT01939548, NCT01806896).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

et al. 2014

Self Cite

View full text Add to dashboard Cite

Phosphodiesterases (PDEs) regulate the levels of the second messengers cAMP and cGMP and are important drug targets. PDE10A is highly enriched in medium spiny neurons of the striatum and is an attractive drug target for the treatment of basal ganglia diseases like schizophrenia, Parkinson's disease, or Huntington's disease. Here we describe the design, synthesis, and application of a variety of chemical biology probes, based on the first clinically tested PDE10A inhibitor MP-10, which were used to characterize the chemoproteomic profile of the clinical candidate in its native environment. A clickable photoaffinity probe was used to measure target engagement of MP-10 and revealed differences between whole cell and membrane preparations. Moreover, our results illustrate the importance of the linker design in the creation of functional probes. Biotinylated affinity probes allowed identification of drug-interaction partners in rodent and human tissue and quantitative mass spectrometry analysis revealed highly specific binding of MP-10 to PDE10A with virtually no off-target binding. The profiling of PDE10A chemical biology probes described herein illustrates a strategy by which high affinity inhibitors can be converted into probes for determining selectivity and target engagement of drug candidates in complex biological matrices from native sources.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…PDE10A is a member of the phosphodiesterase (PDE) family and more specifically is a dual PDE where it is responsible for the degradation of both cAMP and cGMP (Charych, 2014). It is highly expressed in the medium spiny neurons of the striatum, a profile maintained across species (Coskran et al, 2006).…”

Section: Pde10a Inhibitorsmentioning

confidence: 99%

Schizophrenia drug discovery and development in an evolving era: Are new drug targets fulfilling expectations?

Dunlop

Brandon

2015

J Psychopharmacol

View full text Add to dashboard Cite

Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.

show abstract

“…Thus, PDE10A is a unique signaling molecule in being highly expressed in only a single neuronal population and in having a singular molecular signaling role. This localization prompted an intensive effort to determine the role of PDE10A in regulating striatal function and to investigate the potential therapeutic utilities of PDE10A inhibitors (Kehler and Nielsen, 2011 ; Chappie and Verhoest, 2014 ; Charych and Brandon, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

2021

View full text Add to dashboard Cite

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

show abstract

Molecular And Cellular Understanding of PDE10A: A Dual‐Substrate Phosphodiesterase with Therapeutic Potential to Modulate Basal Ganglia Function

Cited by 5 publications

References 74 publications

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

Schizophrenia drug discovery and development in an evolving era: Are new drug targets fulfilling expectations?

PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

Contact Info

Product

Resources

About