Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives

Zhang, Jinfeng; Luo, Ziwei; Duan, Wenwen; Yang, Kexin; Ling, Liuyi; Yan, Wanfeng; Liu, Ruiquan; Wüthrich, Kurt; Jiang, Hualiang; Xie, Conghua; Cheng, Jianjun

doi:10.1016/j.ejmech.2022.114326

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…A 2A AR was shown to be the major target for influencing the immunosuppressive effects of adenosine in tumor microenvironments [52,53]. Detailed structural characterization of A 2A AR is an ongoing part of projects aimed at developing new cancer drugs that target this GPCR [54,55].…”

Section: Discussionmentioning

confidence: 99%

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

et al. 2023

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Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) mediate the actions of two-thirds of the human hormones and neurotransmitters and over one-third of clinically used drugs. Studying the structure and dynamics of human GPCRs in lipid bilayer environments resembling the native cell membrane milieu is of great interest as a basis for understanding structure–function relationships and thus benefits continued drug development. Here, we incorporate the human A2A adenosine receptor (A2AAR) into lipid nanodiscs, which represent a detergent-free environment for structural studies using nuclear magnetic resonance (NMR) in solution. The [15N,1H]-TROSY correlation spectra confirmed that the complex of [u-15N, ~70% 2H]-A2AAR with an inverse agonist adopts its global fold in lipid nanodiscs in solution at physiological temperature. The global assessment led to two observations of practical interest. First, A2AAR in nanodiscs can be stored for at least one month at 4 °C in an aqueous solvent. Second, LMNG/CHS micelles are a very close mimic of the environment of A2AAR in nanodiscs. The NMR signal of five individually assigned tryptophan indole 15N–1H moieties located in different regions of the receptor structure further enabled a detailed assessment of the impact of nanodiscs and LMNG/CHS micelles on the local structure and dynamics of A2AAR. As expected, the largest effects were observed near the lipid–water interface along the intra- and extracellular surfaces, indicating possible roles of tryptophan side chains in stabilizing GPCRs in lipid bilayer membranes.

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Section: Discussionmentioning

confidence: 99%

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

et al. 2023

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“…The mode of action of APYs is multimodal and is deemed to be the reason behind the beneficial effects in treating mood disorders and anxiety. Moreover, novel medications, such as adenosine, histamine, and trace amine-associated receptor ligands, also function through the multimodal stimulatory mechanism of central serotonin, norepinephrine, and/or histamine neurotransmission [56]. The combination of antipsychotic and antidepressant medications has been suggested to work through the same mechanism of central monoamine neurotransmission, leading to a potential combined effect [38,57,58].…”

Section: Apys As Adjuncts To Antidepressants Treat Schizophrenia and ...mentioning

confidence: 99%

Receptors Involved in Mental Disorders and the Use of Clozapine, Chlorpromazine, Olanzapine, and Aripiprazole to Treat Mental Disorders

et al. 2023

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Mental illnesses are a global health challenge, and effective medicines are needed to treat these conditions. Psychotropic drugs are commonly prescribed to manage mental disorders, such as schizophrenia, but unfortunately, they can cause significant and undesirable side effects, such as myocarditis, erectile dysfunction, and obesity. Furthermore, some schizophrenic patients may not respond to psychotropic drugs, a condition called schizophrenia-treatment resistance. Fortunately, clozapine is a promising option for patients who exhibit treatment resistance. Unlike chlorpromazine, scientists have found that clozapine has fewer neurological side effects. Additionally, olanzapine and aripiprazole are well-known for their moderating effects on psychosis and are widely used in clinical practice. To further maximize drug efficacy, it is critical to deeply understand the receptors or signaling pathways central to the nervous system, such as serotonin, histamine, trace amines, dopamine, and G-protein coupled receptors. This article provides an overview of the receptors mentioned above, as well as the antipsychotics that interact with them, such as olanzapine, aripiprazole, clozapine, and chlorpromazine. Additionally, this article discusses the general pharmacology of these medications.

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“…Novel A 2A AR antagonists for cancer immunotherapy continue to be synthesized and developed [ 184 , 185 ], including dual-acting compounds targeting both A 2A ARs and other well-recognized cancer targets such as histone deacetylases [ 186 , 187 ] or CD73 [ 188 ]. In an attempt to mitigate the adverse effects of systemic A 2A AR inhibition and facilitate tumor-specific delivery and activation of A 2A AR antagonists, various innovative approaches utilizing nanotechnologies have been investigated.…”

Section: Ars In Cancermentioning

confidence: 99%

Pharmacology of Adenosine Receptors: Recent Advancements

Vincenzi,

Pasquini,

Contri

et al. 2023

Biomolecules

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Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.

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Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives

Cited by 7 publications

References 25 publications

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

Receptors Involved in Mental Disorders and the Use of Clozapine, Chlorpromazine, Olanzapine, and Aripiprazole to Treat Mental Disorders

Pharmacology of Adenosine Receptors: Recent Advancements

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