Synthesis and Structure–Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3-<i>b</i>]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity

Verdonck, Sven; Pu, Szu-Yuan; Sorrell, F.J.; Elkins, Jon; Froeyen, Matheus; Gao, Ling‐Jie; Prugar, Laura I.; Dorosky, Danielle E.; Brannan, Jennifer M.; Barouch-Bentov, Rina; Knapp, S.; Dye, John M.; Herdewijn, Piet; Einav, Shirit; Jonghe, Steven De

doi:10.1021/acs.jmedchem.9b00136

Cited by 48 publications

(50 citation statements)

References 65 publications

(177 reference statements)

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“…In the past decade, there has been a significant effort to develop small molecules for the treatment of DENV infection, yielding multiple promising candidates with a number of different scaffolds. [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] However, none of these compounds have entered clinical trials for DENV treatment. Interestingly, many of these compounds include common kinase inhibitor scaffolds, such as the oxindole [ 14 ], iso thiazolo[4,3- b ]pyridine [ 15 ] and azaindoles [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…[ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] However, none of these compounds have entered clinical trials for DENV treatment. Interestingly, many of these compounds include common kinase inhibitor scaffolds, such as the oxindole [ 14 ], iso thiazolo[4,3- b ]pyridine [ 15 ] and azaindoles [ 16 ]. Another kinase scaffold with reported anti-DENV activity has been the 4-anilinoquin(az)oline, present in a number of clinically approved kinase inhibitors [ 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

et al. 2021

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Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a series of lead compounds, each occupying a distinct chemical space, including 3-((6-bromoquinolin-4-yl)amino)phenol (12), 6-bromo-N-(5-fluoro-1H-indazol-6-yl)quinolin-4-amine (50) and 6-((6-bromoquinolin-4-yl)amino)isoindolin-1-one (52), with EC50 values of 0.63–0.69 µM for DENV infection. These compound libraries demonstrated very limited toxicity with CC50 values greater than 10 µM in almost all cases. Additionally, the lead compounds were screened for activity against VEEV and demonstrated activity in the low single-digit micromolar range, with 50 and 52 demonstrating EC50s of 2.3 µM and 3.6 µM, respectively. The promising results presented here highlight the potential to further refine this series in order to develop a clinical compound against DENV, VEEV, and potentially other emerging viral threats.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

et al. 2021

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“…The Numb-associated kinases AAK1 and GAK have also been implicated in regulation of virus entry by CME. 32, 36 However, inhibitors of these kinases generally demonstrate antiviral activity at only micromolar concentrations 12 and the antiviral activity often does not track with kinase inhibition. 37, 38 Furthermore, AAK1 inhibition was recently reported to block SARS-CoV-2 virus uptake only in a subset of cells that lack the ACE2 receptor, 39 implicating a mechanism independent of CME.…”

Section: Resultsmentioning

confidence: 99%

“…Our data demonstrate that CSNK2 may also be involved in virus entry through CME (Figure 5), suggesting that β-CoV utilize a common kinase for multiple steps in viral trafficking during their life cycle. The Numb-associated kinases AAK1 and GAK have also been implicated in regulation of virus entry by CME (32, 38). However, inhibitors of these kinases generally demonstrate antiviral activity at only micromolar concentrations (12) and the antiviral activity often does not track with kinase inhibition (39, 40).…”

Section: Discussionmentioning

confidence: 99%

Host kinase CSNK2 is a target for inhibition of pathogenic β-coronaviruses including SARS-CoV-2

Yang¹,

Dickmander

Bayati

et al. 2022

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Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human and murine β-coronaviruses (β-CoV). The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in β-CoV replication. Spike protein uptake was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for development of new broad spectrum anti-β-CoV drugs.

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“…EC 50 for DENV was 8 μM (compound 30 ) vs 0.72 μM (compound 31 ). 67 With respect to kinase selectivity, although not highly selective, optimized candidates presented a better profile than sunitinib ( 2 , Figure 2 ), and they are useful pharmacological tools to be used instead of this drug.…”

Section: Numb-associated Kinases (Naks)mentioning

confidence: 99%

Kinase Inhibitors as Underexplored Antiviral Agents

et al. 2021

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Viral infections are a major health problem; therefore, there is an urgent need for novel therapeutic strategies. Antivirals used to target proteins encoded by the viral genome usually enhance drug resistance generated by the virus. A potential solution may be drugs acting at host-based targets since viruses are dependent on numerous cellular proteins and phosphorylation events that are crucial during their life cycle. Repurposing existing kinase inhibitors as antiviral agents would help in the cost and effectiveness of the process, but this strategy usually does not provide much improvement, and specific medicinal chemistry programs are needed in the field. Anyway, extensive use of FDA-approved kinase inhibitors has been quite useful in deciphering the role of host kinases in viral infection. The present perspective aims to review the state of the art of kinase inhibitors that target viral infections in different development stages.

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Synthesis and Structure–Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3-b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity

Abstract: There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor associated kinase 1 (AAK1) is a cellular serine/threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and *

Cited by 48 publications

References 65 publications

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

Host kinase CSNK2 is a target for inhibition of pathogenic β-coronaviruses including SARS-CoV-2

Kinase Inhibitors as Underexplored Antiviral Agents

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