Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

Gurney, Mark E.; Nugent, Richard A.; Mo, Xuesheng; Sindac, Janice A.; Hagen, Timothy J.; Fox, David; O’Donnell, James M.; Zhang, C.; Xu, Yong; Zhang, H.T.; Groppi, Vincent E.; Bailie, Margot J.; White, Richard E.; Romero, Donna L.; Vellekoop, A. Samuel; Walker, John R.; Surman,; Zhu, Lizhe; Campbell, Robert F.

doi:10.1021/acs.jmedchem.9b00193

Cited by 54 publications

(71 citation statements)

References 83 publications

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“…The data from us and others have shown that chronic antidepressant treatment increased adenylyl cyclase (AC) activity and cAMP in cells [31, 47, 60]. Phosphodiesterase 4 (a cAMP-specific isoform) inhibitors show antidepressant effects in both patient and rodent models [61–64]. Activation of CREB via the cAMP-PKA signaling pathway is thought to mediate the therapeutic effects of antidepressants [24].…”

Section: Discussionmentioning

confidence: 99%

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Wang

Sheridan

et al. 2020

Preprint

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30Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled 31 trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious 32 for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs 33 potential therapeutic properties remain unknown. There are suggestions in the literature that glial 34 hypofunction is associated with depressive symptoms and that antidepressants may normalize 35 glial function. In this study, iPSC-derived neuronal stem cell lines were generated from 36 individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells 37 (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), 38 docosahexaenoic acid (DHA) and stearic acid (SA). During astrocyte differentiation, we found 39 that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and 40 GDNF production were increased in the astrocytes derived from patients subsequent to n-3 41 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity 42 (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when 43 these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-44 3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF 45 and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these 46 results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of 47 some antidepressants by increasing production of neurotrophic factors. The CREB-dependence 48 and cAMP independence of this process suggests a manner in which n-3 PUFA could augment 49 antidepressant effects. These data also suggest a role for astrocytes in both MDD and 50 antidepressant action. 51 52 53Major depressive disorder (MDD) is the most common psychiatric disorder, with almost 54 one in six individuals experiencing at least one depressive episode at some point in their lifetime. 55It is currently the leading cause of disability worldwide [1, 2]. While effective treatments exist, 56 about one third of patients treated with antidepressants do not reach symptomatic remission [3, 57 4]. While some of these non-remitters may respond to ketamine or other rescue strategies, 58 additional therapeutic options are needed. 59Brain regions and even cell-types contributing to MDD are not well established [4]. 60Evidence from clinical, preclinical and post-mortem studies suggests that dysfunction and 61 degeneration of astrocytes may be one of potential candidates, and astrocytes may also represent 62 a potential therapeutic target for MDD [5][6][7][8]. Antidepressants, including SSRIs and ketamine, 63 increase brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor 64 (GDNF) expression in primary cultured animal astrocytes [9][10][11]. Substantial evidence suggested 65 that astrocytes might be the main resource of antidepressant...

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Section: Discussionmentioning

confidence: 99%

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Wang

Sheridan

et al. 2020

Preprint

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“…This study demonstrates that a phosphodiesterase-4D allosteric inhibitor protects against memory loss and neuronal atrophy induced by microinjection of oligomeric A β 1–42 into the hippocampus of hPDE4D mice. The use of hPDE4D mice allowed us to explore PDE4D pharmacology at doses of BPN14770 that do not appreciably inhibit PDE4 subtypes A and B, the other subtypes of PDE4 present in the brain (Zhang et al, 2018; Gurney et al, 2019). Very low doses BPN14770 (0.01 and 0.03 mg/kg) prevented the impairment of memory acquisition and retrieval in the MWM and Y-maze tests caused by microinjection of oligomeric A β 1–42 .…”

Section: Discussionmentioning

confidence: 99%

“…Aggregated A β 1–42 (0.4 μ g in 1 μ l/side; rPeptide) or ACF was microinjected bilaterally into the CA1 of the hippocampus through an injection cannula in a volume of 1 μ l/side over a 5-minute period. BPN14770 was synthesized and prepared as previously described (Gurney et al, 2019). The protein kinase A (PKA) inhibitor N -[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-89) (Sigma-Aldrich) was prepared in 0.9% sterile saline to a final concentration of 5 μ M for bilateral injection into the CA1 of the hippocampus (1 μ l/side).…”

Section: Methodsmentioning

confidence: 99%

“…Although rolipram has been explored in patients with major depression, the compound is highly emetic, which prevents dosing in humans within the desired therapeutic range (Hebenstreit et al, 1989; Fleischhacker et al, 1992). Subtype-selective PDE4D allosteric inhibitors, in contrast to rolipram, achieve selectivity for PDE4D due to a single amino acid difference in the allosteric binding site on a regulatory domain known as upstream conserved region 2 (Burgin et al, 2010; Gurney et al, 2019). The key selectivity residue is a phenylalanine in PDE4D and a tyrosine in PDE4 subtypes A–C.…”

Section: Introductionmentioning

confidence: 99%

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Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Cui

Zhang

Zheng

et al. 2019

J Pharmacol Exp Ther

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Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Ab 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Ab impairment. Microinjection of oligomeric Ab 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Ab-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brainderived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Ab-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Ab 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Ab 1-42 neurotoxicity.

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“…Recently, the allosteric inhibitors targeting the sites out of the catalytic pocket are becoming an alternative strategy to develop the efficient and safe therapeutic agents [11,12]. For example, the subtype selective PDE4D allosteric inhibitor, BPN14770 exhibited the reduced vascular toxicity over earlier PDE4 inhibitors that lacked the subtype selectivity [13], and compound 8t as the allosteric inhibitor of phosphoglycerate mutase 1 was demonstrated to delay tumor growth in H1299 xenograft model without the obvious toxicity [14]. Identification of allosteric pockets is the basis for the design of allosteric inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

Zhang

et al. 2020

Molecules

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Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

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Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

Cited by 54 publications

References 83 publications

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

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