Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D

Allosteric Regulation / drug effects Animals Antineoplastic Agents / chemistry CHO Cells Cricetinae Cricetulus Dopamine D2 Receptor Antagonists / chemistry Dose-Response Relationship, Drug HEK293 Cells Humans Imidazoles / chemistry Protein Binding / drug effects Protein Structure, Secondary Pyridines / chemistry Pyrimidines / chemistry Receptors, Dopamine D2 / chemistry

Journal

Molecular pharmacology
ISSN: 1521-0111
Titre abrégé: Mol Pharmacol
Pays: United States
ID NLM: 0035623

Informations de publication

Date de publication:
10 2021
Historique:
received: 11 06 2021
accepted: 26 07 2021
pubmed: 7 8 2021
medline: 11 11 2021
entrez: 6 8 2021
Statut: ppublish

Résumé

ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its potency for antiproliferative effects. Curve-shift experiments using D2R-mediated

Identifiants

DOI: 10.1124/molpharm.121.000336 PMID: 34353882 PMC: PMC8626643
pubmed: 34353882
pii: molpharm.121.000336
doi: 10.1124/molpharm.121.000336
pmc: PMC8626643
doi:

Substances chimiques

Antineoplastic Agents 0
DRD2 protein, human 0
Dopamine D2 Receptor Antagonists 0
Imidazoles 0
Pyridines 0
Pyrimidines 0
Receptors, Dopamine D2 0
TIC10 compound 9U35A31JAI

Types de publication

Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

372-387

Subventions

Organisme : Intramural NIH HHS
ID : ZIA DA000609
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA NS002263
Pays : United States

Informations de copyright

U.S. Government work not protected by U.S. copyright.

Références

Oncotarget. 2014 Feb 28;5(4):882-93
pubmed: 24658464
Cell Syst. 2021 Apr 21;12(4):324-337.e5
pubmed: 33667409
ACS Chem Biol. 2019 Aug 16;14(8):1780-1792
pubmed: 31339684
Nat Commun. 2019 Nov 19;10(1):5221
pubmed: 31745082
Pharmacol Rev. 2011 Mar;63(1):182-217
pubmed: 21303898
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3577-82
pubmed: 11248120
Sci Signal. 2018 Dec 04;11(559):
pubmed: 30514808
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
pubmed: 4202581
Proc Natl Acad Sci U S A. 2020 May 19;117(20):11085-11096
pubmed: 32358191
Arch Pharm Res. 2018 Apr;41(4):384-408
pubmed: 29556831
CNS Drugs. 2021 Mar;35(3):253-264
pubmed: 33651366
Elife. 2020 Jan 27;9:
pubmed: 31985399
Clin Cancer Res. 2019 Apr 1;25(7):2305-2313
pubmed: 30559168
Trends Pharmacol Sci. 2007 Aug;28(8):382-9
pubmed: 17629965
Pharmacol Rev. 2015;67(1):198-213
pubmed: 25527701
Cell Cycle. 2018;17(4):468-478
pubmed: 29157092
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13485-90
pubmed: 16938864
Nature. 2020 Aug;584(7819):125-129
pubmed: 32528175
PLoS Comput Biol. 2018 Jan 16;14(1):e1005948
pubmed: 29337986
Clin Cancer Res. 2017 Aug 1;23(15):4163-4169
pubmed: 28331050
J Biol Chem. 2007 Apr 6;282(14):10576-84
pubmed: 17283075
Neoplasia. 2020 Dec;22(12):725-744
pubmed: 33142238
ACS Chem Neurosci. 2020 Oct 21;11(20):3309-3320
pubmed: 32969645
Neuropsychopharmacology. 2011 Feb;36(3):551-8
pubmed: 20980993
Cell Signal. 2018 Jan;41:75-81
pubmed: 28716664
Sci Rep. 2019 Dec 10;9(1):18695
pubmed: 31822725
Biochem Pharmacol. 2018 Feb;148:315-328
pubmed: 29325769
J Pharmacol Exp Ther. 2019 Jul;370(1):111-126
pubmed: 31000578
J Neurosci. 2019 Mar 13;39(11):1982-1993
pubmed: 30651332
J Chem Theory Comput. 2019 Mar 12;15(3):1863-1874
pubmed: 30768902
Nat Commun. 2020 Dec 22;11(1):6442
pubmed: 33353947
Cancer Cell. 2019 May 13;35(5):721-737.e9
pubmed: 31056398
Oncogene. 2018 Oct;37(41):5492-5507
pubmed: 29887596
PLoS One. 2015 Nov 18;10(11):e0143082
pubmed: 26580220
Nature. 2018 Mar 8;555(7695):269-273
pubmed: 29466326
Cell. 2012 Jun 8;149(6):1284-97
pubmed: 22632761
Biol Psychiatry. 2001 Dec 1;50(11):873-83
pubmed: 11743942
J Cell Physiol. 2016 Feb;231(2):345-56
pubmed: 26081799
Int J Cancer. 2010 May 1;126(9):2112-22
pubmed: 19795457
Mol Pharmacol. 2018 Oct;94(4):1197-1209
pubmed: 30068735
Oncol Lett. 2016 Feb;11(2):1281-1286
pubmed: 26893731
Front Oncol. 2013 Oct 04;3:241
pubmed: 24109588
Oncotarget. 2014 Dec 30;5(24):12728-37
pubmed: 25587031
Front Cell Neurosci. 2018 Sep 03;12:289
pubmed: 30233327
Mol Pharmacol. 2015 Jul;88(1):171-80
pubmed: 25904553
J Med Chem. 2020 May 28;63(10):5526-5567
pubmed: 32342685
ACS Chem Biol. 2019 May 17;14(5):1020-1029
pubmed: 31021596
Sci Signal. 2020 Feb 04;13(617):
pubmed: 32019899
Oncol Lett. 2017 Mar;13(3):1223-1227
pubmed: 28454238
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13656-61
pubmed: 18768802
PLoS One. 2011;6(5):e20123
pubmed: 21629661
Trends Pharmacol Sci. 1992 Feb;13(2):61-9
pubmed: 1561715
FEBS Lett. 2020 Dec;594(24):4201-4232
pubmed: 33270228
Sci Transl Med. 2013 Feb 6;5(171):171ra17
pubmed: 23390247

Auteurs

R Benjamin Free (RB)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Caroline A Cuoco (CA)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Bing Xie (B)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Yoon Namkung (Y)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Varun V Prabhu (VV)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Blair K A Willette (BKA)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Marilyn M Day (MM)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Marta Sanchez-Soto (M)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

J Robert Lane (JR)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Stéphane A Laporte (SA)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Lei Shi (L)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.).

Joshua E Allen (JE)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.) sibleyd@ninds.nih.gov jallen@chimerix.com.

David R Sibley (DR)

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., C.A.C., B.K.A.W., M.M.D., M.S-S., D.R.S.); Chimerix, Inc., Durham, North Carolina (V.V.P., J.E.A.); Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (B.X., L.S.); Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Canada (Y.N., S.A.P.); and Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Nottingham, Midlands, United Kingdom (J.R.L.) sibleyd@ninds.nih.gov jallen@chimerix.com.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Régulation allostérique › Pharmacological Characterization of the...
questionsmedicales.fr › Eucaryotes › Animaux › Pharmacological Characterization of the...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Pharmacological Characterization of the...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules CHO › Pharmacological Characterization of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Arvicolinae › Cricetinae › Pharmacological Characterization of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Arvicolinae › Cricetinae › Cricetulus › Pharmacological Characterization of the...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Agents neuromédiateurs › Agents dopaminergiques › Antagonistes de la dopamine › Antagonistes du récepteur D2 de la dopamine › Pharmacological Characterization of the...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Pharmacological Characterization of the...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Pharmacological Characterization of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Pharmacological Characterization of the...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Pharmacological Characterization of the...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Pharmacological Characterization of the...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure secondaire des protéines › Pharmacological Characterization of the...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Pharmacological Characterization of the...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Pharmacological Characterization of the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs catécholaminergiques › Récepteurs dopaminergiques › Récepteur D2 de la dopamine › Pharmacological Characterization of the...