Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

Olson, Margaret E.; Abate-Pella, Daniel; Perkins, Angela L.; Li, Ming; Carpenter, Michael A.; Rathore, Anurag S.; Harris, Reuben S.; Harki, Daniel A.

doi:10.1021/acs.jmedchem.5b00930

Cited by 24 publications

(25 citation statements)

References 47 publications

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“…Interestingly, in this study three of the five initial hits identified were found to inhibit the RGS17-G␣ o interaction through decomposition products. This finding and previous work from Olson et al (111) indicate the decomposition potential for compounds containing furan functionalities in chemical library storage and usage conditions (108). This example highlights the often-repeated cautionary tale of chemical compound library stability and the critical need for structural verification of initial hit compounds (109).…”

Section: Efforts In Rgs Drug Discoverysupporting

confidence: 66%

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

O’Brien

Wilkinson

Roman

2019

Journal of Biological Chemistry

101

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Edited by Henrik G. Dohlman G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.

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Section: Efforts In Rgs Drug Discoverysupporting

confidence: 66%

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

O’Brien

Wilkinson

Roman

2019

Journal of Biological Chemistry

101

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“…Two of these transformations result in the formation of α,β unsaturations through hydrolytic opening of the endoperoxide resulting in the formation of fumarate moieties. 31…”

Section: Resultsmentioning

confidence: 99%

“…A recent report by Olson et al detailed the identification of a chemical structure prone to instability in screening libraries. 31 Additionally, these authors found that this chemical structure was enriched in screening libraries. Therefore, it seems in the best interest of the field to identify compound structures prone to instability to prevent the misallocation of resources toward these chemical entities.…”

Section: Introductionmentioning

confidence: 99%

Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

et al. 2018

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Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein-coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers. A screen of over 60,000 small molecules led to the identification of five hit compounds that inhibit the RGS17-Gα protein-protein interaction. Chemical and biochemical characterization demonstrated that three of these hits inhibited the interaction through the decomposition of parent compound into reactive products under normal chemical library storage/usage conditions. Compound substructures susceptible to decomposition are reported and the decomposition process characterized, adding to the armamentarium of tools available to the screening field, allowing for the conservation of resources in follow-up efforts and more efficient identification of potentially decomposed compounds. Finally, analogues of one hit compound were tested, and the results establish the first ever structure-activity relationship (SAR) profile for a small-molecule inhibitor of RGS17.

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“…Compound A is an isoxazole with a furan ring in the 2-position. It has been reported that furans tend to undergo oxidative decomposition in air (49,50). To avoid such undesirable properties, three analogues of compound A in which the furan ring was replaced with a methoxy phenyl group were designed, synthesized, and tested for their ability to block HSV-1 infection.…”

Section: Identification Of Hts Hitsmentioning

confidence: 99%

Discovery of Small-Molecule Inhibitors Targeting the E3 Ubiquitin Ligase Activity of the Herpes Simplex Virus 1 ICP0 Protein Using an In Vitro High-Throughput Screening Assay

Deschamps

Waisner

Dogrammatzis

et al. 2019

J Virol

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Herpes simplex virus 1 (HSV-1) has infected more than 80% of the population. Reactivation of the virus causes diseases ranging in severity from benign cold sores to fatal encephalitis. Current treatments involve viral DNA replication inhibitors, but the emergence of drug-resistant mutants is observed frequently, highlighting the need for novel antiviral therapies. Infected cell protein 0 (ICP0) of HSV-1 is encoded by an immediate early gene and plays a fundamental role during infection, because it enables viral gene expression and blocks antiviral responses. One mechanism by which ICP0 functions is through an E3 ubiquitin ligase activity that induces the degradation of targeted proteins. A ΔICP0 virus or mutants with deficiencies in E3 ligase activity cannot counteract beta interferon (IFN-β)-induced restriction of viral infection, are highly immunogenic, are avirulent, and fail to spread. Thus, small molecules interfering with essential and conserved ICP0 functions are expected to compromise HSV-1 infection. We have developed a high-throughput screening assay, based on the autoubiquitination properties of ICP0, to identify small-molecule inhibitors of ICP0 E3 ubiquitin ligase activity. Through a pilot screening procedure, we identified nine compounds that displayed dose-dependent inhibitory effects on ICP0 but not on Mdm2, a control E3 ubiquitin ligase. Following validation, one compound displayed ICP0-dependent inhibition of HSV-1 infection. This compound appeared to bind ICP0 in a cellular thermal shift assay, it blocked ICP0 self-elimination, and it blocked wild-type but not ICP0-null virus gene expression. This scaffold displays specificity and could be used to develop optimized ICP0 E3 ligase inhibitors. IMPORTANCE Since acyclovir and its derivatives were launched for herpesviruses control almost four decades ago, the search for novel antivirals has waned. However, as human life expectancy has increased, so has the number of immunocompromised individuals who receive prolonged treatment for HSV recurrences. This has led to an increase in unresponsive patients due to acquired viral drug resistance. Thus, novel treatments need to be explored. Here we explored the HSV-1 ICP0 E3 ligase as a potential antiviral target because (i) ICP0 is expressed before virus replication, (ii) it is essential for infection in vivo, (iii) it is required for efficient reactivation of the virus from latency, (iv) inhibition of its E3 ligase activity would sustain host immune responses, and (v) it is shared by other herpesviruses. We report a compound that inhibits HSV-1 infection in an ICP0-dependent manner by inhibiting ICP0 E3 ligase activity.

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Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

Cited by 24 publications

References 47 publications

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

Discovery of Small-Molecule Inhibitors Targeting the E3 Ubiquitin Ligase Activity of the Herpes Simplex Virus 1 ICP0 Protein Using an In Vitro High-Throughput Screening Assay

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