Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D<sub>2</sub>Dopamine Receptor

Free, R. Benjamin; Cuoco, Caroline A.; Xie, Bing; Namkung, Yoon; Prabhu, Varun V.; Willette, Blair K. A.; Day, Marilyn M.; Sánchez-Soto, Marta; Lane, J. Robert; Laporte, Stéphane A.; Shi, Lei; Allen, Joshua E.; Sibley, David R.

doi:10.1124/molpharm.121.000336

Cited by 23 publications

(20 citation statements)

References 57 publications

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“…This includes effects on cell growth, OCR, and mitochondrial protein level as determined by immunoblotting. While ONC201, at concentrations far higher than that is necessary to activate ClpP or inhibit cell growth, has shown effects on dopamine receptors D2/D3(56,59), our data(26) and that of others(25,27) strongly argues against a major role of the dopamine receptors in growth inhibition.…”

Section: Discussioncontrasting

confidence: 43%

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Fennell

Aponte‐Collazo

Wynn

et al. 2022

Preprint

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We recently described the identification of a new class of small molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. One of these compounds (TR-107) was selected for further studies because of excellent potency, specificity and drug-like properties. Examination of TR-107 effects in Triple Negative Breast Cancer (TNBC) cell models showed growth inhibition in the low nanomolar range, equipotent to paclitaxel, in a ClpP-dependent manner. TR-107 reduced specific mitochondrial proteins including OXPHOS and TCA cycle components, in a time, dose and ClpP-dependent manner. Seahorse XF Analysis and glucose deprivation experiments confirmed inactivation of OXPHOS and demonstrated an increased dependence on glycolysis following TR-107 exposure. The pharmacokinetic properties of TR-107 were compared to other known ClpP activators including ONC201 and ONC212. TR-107 displayed excellent exposure and serum t1/2 after oral administration. Using an orthotopic xenograft murine model of MDA-MB-231 cells, the anti-tumor response to TR-107 was investigated. Oral administration of TR-107 resulted in reduction in tumor volume and extension of survival in the treated vs. vehicle control groups. In summary, these studies describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.

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Section: Discussioncontrasting

confidence: 43%

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Fennell

Aponte‐Collazo

Wynn

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This includes effects on cell growth, OCR, and mitochondrial protein level as determined by immunoblotting. While ONC201, at concentrations far higher than that is necessary to activate ClpP or inhibit cell growth, has shown effects on dopamine receptors D2/D3, 55,59 our data 24 and that of others 23,25 strongly argues against a major role of the dopamine receptors in growth inhibition.…”

Section: Discussionmentioning

confidence: 55%

Characterization of TR‐107, a novel chemical activator of the human mitochondrial protease ClpP

Fennell

Aponte‐Collazo

Wynn

et al. 2022

Pharmacology Res & Perspec

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“…The greatest effects of D 2 R mutations to reduce this increase in SB269,652 potency upon pre-application was observed with E95A and S193A. Interactions with E95 have consistently been found to be important for the allosteric actions of SB269,652 and for the binding of other allosteric D 2 R ligands [ 25 , 26 ]. Notably, in the present experiments, an E95A mutation reduced the shift in potency upon SB269,652 pre-application to about two-fold.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

Ågren

Sahlholm

2021

Biomedicines

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SB269,652 has been described as the first negative allosteric modulator (NAM) of the dopamine D2 receptor (D2R), however, the binding mode and allosteric mechanism of action of this ligand remain incompletely understood. SB269,652 comprises an orthosteric, primary pharmacophore and a secondary (or allosteric) pharmacophore joined by a hydrophilic cyclohexyl linker and is known to form corresponding interactions with the orthosteric binding site (OBS) and the secondary binding pocket (SBP) in the D2R. Here, we observed a surprisingly low potency of SB269,652 to negatively modulate the D2R-mediated activation of G protein-coupled inward-rectifier potassium channels (GIRK) and decided to perform a more detailed investigation of the interaction between dopamine and SB269,652. The results indicated that the SB269,652 inhibitory potency is increased 6.6-fold upon ligand pre-incubation, compared to the simultaneous co-application with dopamine. Mutagenesis experiments implicated both S193 in the OBS and E95 in the SBP in the effect of pre-application. The present findings extend previous knowledge about how SB269,652 competes with dopamine at the D2R and may be useful for the development of novel D2R ligands, such as antipsychotic drug candidates.

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Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D₂Dopamine Receptor

Cited by 23 publications

References 57 publications

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Characterization of TR‐107, a novel chemical activator of the human mitochondrial protease ClpP

Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

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Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D2Dopamine Receptor

Cited by 23 publications

References 57 publications

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

Characterization of TR‐107, a novel chemical activator of the human mitochondrial protease ClpP

Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

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Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the D₂Dopamine Receptor