Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Meza‐Avina, Maria Elena; Lingerfelt, Mary A.; Console-Bram, Linda; Gamage, Thomas F.; Sharir, Haleli; Gettys, Kristen E.; Hurst, Dow P.; Kotsikorou, Evangelia; Shore, Derek M.; Caron, Marc G.; Rao, Narasinga; Barak, Larry S.; Abood, Mary E.; Reggio, Patricia H.; Croatt, Mitchell P.

doi:10.1016/j.bmcl.2016.02.030

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…In particular, GPR55 is highly expressed in TNBC cell lines, and its activation correlates with cancer proliferation and invasion. − Despite increasing evidence, the paucity of specific ligands of GPR55 has limited its study as anticancer target. Most of them possess electronegative groups and pendant aromatic or heterocyclic rings that make critical hydrogen-bonding and aromatic interactions with specific residues in the receptor binding pocket. − Based on these data, the design and the discovery of new potent ligands of GPR55 may be the key for TNBC targeted therapies …”

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confidence: 99%

Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55

Badolato

Carullo

Caroleo

et al. 2019

ACS Med. Chem. Lett.

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A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, 2a and 3a inhibited the proliferation of MDA-MB-231 cells (EC 50 = 1.6 and 2.7 μM, respectively), compared to primary human breast cells MCF10A. Furthermore, they did not affect the viability of peripheral blood mononuclear cells (PBMC), suggesting their potential safer use for cancer treatment. Recently, correlations have emerged between the expression of G protein-coupled receptor 55 (GPR55) and both triple-negative breast cancer development and invasion, making it a promising target for the development of targeted therapies. Based on this evidence, molecular docking studies supported the hypothesis of binding to GPR55, and pharmacological tests suggested that compound 3a could exert its antiproliferative activity acting as a GPR55 inverse agonist.

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confidence: 99%

Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55

Badolato

Carullo

Caroleo

et al. 2019

ACS Med. Chem. Lett.

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“…17 The β-arrestin assay was run using CHO-K1 cells stably expressing GPR55, fused with a β-galactosidase enzyme fragment, and β-arrestin fused to an N-terminal deletion mutant of β-galactosidase (DiscoverX) in the PathHunter® β -arrestin assay as previously published. 32 Activation of GPR55 induces β-arrestin recruitment, forcing complementation of the two β-galactosidase enzyme fragments. Levels of this active enzyme are a direct result of GPR55 activation and are quantitated using chemiluminescent PathHunter® detection reagents containing the β-galactoside substrate.…”

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confidence: 99%

Design, synthesis and biological evaluation of GPR55 agonists

Fakhouri

Cook

Al‐Huniti

et al. 2017

Bioorganic & Medicinal Chemistry

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GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.

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“…The inhibition and/or non-engagement of β-arrestin signaling is intriguing as β-arrestin is involved in multiple protein interaction networks involved in tumor development, metastasis, and transcriptional regulation 85 – 87 . It is important to note that GPR55 activation also results in β-arrestin recruitment to this GPCR and associated increases in MEK/ERK signaling 88 , 89 . Both ( R , S ′)-MNF and ( R , R ′)-MNF effectively inhibit GPR55 activation, which may be the source of some of their effects on tumor growth and viability.…”

Section: Discussionmentioning

confidence: 99%

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist

Wnorowski

Dudzik

Bernier

et al. 2022

Sci Rep

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Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S′)-4′-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased β2-adrenergic receptor (β2-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β2-AR in (R,S′)-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S′)-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S′)-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased β2-AR/Gαs/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S′)-MNF administration significantly reduced PANC-1 tumor growth and circulating l-lactate concentrations. Global metabolic profiling of (R,S′)-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S′)-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β2-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

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Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Cited by 6 publications

References 14 publications

Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55

Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55

Design, synthesis and biological evaluation of GPR55 agonists

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist

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