Cyclin G

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 34980 Experts worldwide ranked by ideXlab platform

Christopher R. M. Asquith - One of the best experts on this subject based on the ideXlab platform.

Steven De Jonghe - One of the best experts on this subject based on the ideXlab platform.

  • discovery of 3 phenyl and 3 n piperidinyl isothiazolo 4 3 b pyridines as hiGhly potent inhibitors of Cyclin G associated kinase
    European Journal of Medicinal Chemistry, 2021
    Co-Authors: Belen Martinezgualda, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Sirle Saul, Dominique Schols, Steven De Jonghe
    Abstract:

    Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of Cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety Generated potent GAK inhibitors with IC50 values in a low nanomolar ranGe. This potent GAK bindinG affinity was rationalized by molecular modellinG demonstratinG that the carboxamide moiety enGaGes in an extra hydroGen bond with GAK. Moreover, this new series of compounds was also endowed with antiviral activity aGainst denGue virus, hiGhliGhtinG the potential utility of GAK as a tarGet for the development of antiviral druGs.

  • structure activity relationship study of the pyridine moiety of isothiazolo 4 3 b pyridines as antiviral aGents tarGetinG Cyclin G associated kinase
    Bioorganic & Medicinal Chemistry, 2020
    Co-Authors: Belen Martinezgualda, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Steven De Jonghe
    Abstract:

    Previously, we reported the discovery of 3,6-disubstituted isothiazolo[4,3-b]pyridines as potent and selective Cyclin G-associated kinase (GAK) inhibitors with promisinG antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK bindinG affinity and antiviral activity aGainst denGue virus.

  • Cyclin G associated kinase Gak affinity and antiviral activity studies of a series of 3 c substituted isothiazolo 4 3 b pyridines
    European Journal of Medicinal Chemistry, 2019
    Co-Authors: Randy Wouters, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Eveline Lescrinier, Steven De Jonghe
    Abstract:

    Cyclin G-associated kinase (GAK) is a cellular reGulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which reGulates intracellular traffickinG of denGue virus durinG early and late staGes of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promisinG antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4,3-b]pyridines with a carbon-linked substituent at position 3 is described by the application of reGioselective Suzuki and SonoGashira couplinG reactions. A derivative with a 3,4-dimethoxyphenyl residue at position 3 demonstrates low nanomolar bindinG affinity for GAK and antiviral activity aGainst denGue virus. These findinGs reveal that appropriate substitution of a phenyl moiety at position 3 of the scaffold can improve GAK bindinG affinity.

  • a scaffold hoppinG strateGy toward the identification of inhibitors of Cyclin G associated kinase
    ChemMedChem, 2019
    Co-Authors: Randy Wouters, Piet Herdewijn, Junjun Tian, Steven De Jonghe
    Abstract:

    We recently reported the discovery of isothiazolo[4,3-b]pyridine-based inhibitors of Cyclin G associated kinase (GAK) displayinG low nanomolar bindinG affinity for GAK and demonstratinG broad-spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold-hoppinG approach was applied startinG from two different isothiazolo[4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar ranGe that can serve as chemical startinG points for the discovery of GAK inhibitors based on a different scaffold.

  • optimization of isothiazolo 4 3 b pyridine based inhibitors of Cyclin G associated kinase Gak with broad spectrum antiviral activity
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Randy Wouters, Piet Herdewijn, Rina Barouchbentov, Jef Rozenski, Stanford Schor, Laura I. Prugar, Jennifer M. Brannan, John M. Dye, Cecilia M Obrien, Steven De Jonghe
    Abstract:

    There is an urGent need for strateGies to combat denGue and other emerGinG viral infections. We reported that Cyclin G-associated kinase (GAK), a cellular reGulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, reGulates intracellular traffickinG of multiple unrelated RNA viruses durinG early and late staGes of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leadinG to the discovery of novel isothiazolo[4,3-b]pyridines that maintain hiGh GAK affinity and selectivity. These compounds demonstrate improved in vitro activity aGainst denGue virus, includinG in human primary dendritic cells, and efficacy aGainst the unrelated Ebola and chikunGunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findinGs demonstrate the potential utility of a GAK-tarGeted...

Jonathan M. Elkins - One of the best experts on this subject based on the ideXlab platform.

  • tarGetinG the water network in Cyclin G associated kinase Gak with 4 anilino quin az oline inhibitors
    ChemMedChem, 2020
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Carrow I. Wells, Timothy M. Willson, Graham J Tizzard, Antti Poso, Tuomo Laitinen
    Abstract:

    Water networks within kinase inhibitor desiGn and more widely within druG discovery are Generally poorly understood. The successful tarGetinG of these networks prospectively has Great promise for all facets of inhibitor desiGn, includinG potency and selectivity for the tarGet. Herein, we describe the desiGn and testinG of a tarGeted library of 4-anilinoquin(az)olines for use as inhibitors of Cyclin G-associated kinase (GAK). GAK cellular tarGet enGaGement assays, ATP bindinG-site modellinG and extensive water mappinG provide a clear route to access potent inhibitors for GAK and beyond.

  • tarGetinG the water network in Cyclin G associated kinase Gak with 4 anilino quin az oline inhibitors
    bioRxiv, 2020
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Carrow I. Wells, Timothy M. Willson, Graham J Tizzard, Antti Poso, Tuomo Laitinen
    Abstract:

    Water networks within kinase inhibitor desiGn and more widely within druG discovery are Generally poorly understood. The successful tarGetinG of these networks prospectively has Great promise for all facets of inhibitor desiGn, includinG potency and selectivity on tarGet. Here we describe the desiGn and testinG of a tarGeted library of 4-anilinoquinolines for use as inhibitors of the Cyclin G associated kinase (GAK). The GAK cellular tarGet enGaGement assays, ATP bindinG site modellinG and extensive water mappinG provide a clear route to access potent inhibitors for GAK and beyond.

  • Development of SGC-GAK-1 as an orally active in vivo probe for Cyclin G associated kinase throuGh cytochrome P450 inhibition
    2019
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Tuomo Laitinen, Jonathan M. Elkins, Julie E. Pickett, Carrow I. Wells, Timothy M. Willson, William J. Zuercher
    Abstract:

    Abstract SGC-GAK-1 (1), a potent, selective, cell-active chemical probe for Cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limitinG its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also Greatly improved plasma exposure of 1 in mice, supportinG its use as a chemical probe to study the in vivo bioloGy of GAK inhibition.

  • sGc Gak 1 a chemical probe for Cyclin G associated kinase Gak
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Benedicttilman Berger, Jing Wan, Stephen J Capuzzi, Daniel J Crona, David H Drewry, Michael P East
    Abstract:

    We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of Cyclin G-associated kinase (GAK), toGether with a structurally related neGative control SGC-GAK-1N (14). 11 was hiGhly selective in an in vitro kinome-wide screen, but cellular enGaGement assays defined RIPK2 as a collateral tarGet. We identified 18 as a potent RIPK2 inhibitor lackinG GAK activity. ToGether, this chemical probe set can be used to interroGate GAK cellular bioloGy.

  • sGc Gak 1 a chemical probe for Cyclin G associated kinase Gak
    bioRxiv, 2018
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Benedicttilman Berger, Jing Wan, Michael P East, O Fedorov, P H C Godoi, Debra Hunter, S Knapp
    Abstract:

    We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of Cyclin G associated kinase (GAK), toGether with a structurally-related neGative control SGC-GAK-1N (14). SGC-GAK-1 is hiGhly selective in a kinome-wide screen, but cellular enGaGement assays defined RIPK2 as a collateral tarGet. We identified 18 as a potent inhibitor of RIPK2 lackinG GAK activity. ToGether, the chemical probe set of 11, 14, and 18 can be used to interroGate the cellular bioloGy of GAK inhibition.

Piet Herdewijn - One of the best experts on this subject based on the ideXlab platform.

  • discovery of 3 phenyl and 3 n piperidinyl isothiazolo 4 3 b pyridines as hiGhly potent inhibitors of Cyclin G associated kinase
    European Journal of Medicinal Chemistry, 2021
    Co-Authors: Belen Martinezgualda, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Sirle Saul, Dominique Schols, Steven De Jonghe
    Abstract:

    Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of Cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety Generated potent GAK inhibitors with IC50 values in a low nanomolar ranGe. This potent GAK bindinG affinity was rationalized by molecular modellinG demonstratinG that the carboxamide moiety enGaGes in an extra hydroGen bond with GAK. Moreover, this new series of compounds was also endowed with antiviral activity aGainst denGue virus, hiGhliGhtinG the potential utility of GAK as a tarGet for the development of antiviral druGs.

  • structure activity relationship study of the pyridine moiety of isothiazolo 4 3 b pyridines as antiviral aGents tarGetinG Cyclin G associated kinase
    Bioorganic & Medicinal Chemistry, 2020
    Co-Authors: Belen Martinezgualda, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Steven De Jonghe
    Abstract:

    Previously, we reported the discovery of 3,6-disubstituted isothiazolo[4,3-b]pyridines as potent and selective Cyclin G-associated kinase (GAK) inhibitors with promisinG antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK bindinG affinity and antiviral activity aGainst denGue virus.

  • Cyclin G associated kinase Gak affinity and antiviral activity studies of a series of 3 c substituted isothiazolo 4 3 b pyridines
    European Journal of Medicinal Chemistry, 2019
    Co-Authors: Randy Wouters, Piet Herdewijn, Mathy Froeyen, Shirit Einav, Eveline Lescrinier, Steven De Jonghe
    Abstract:

    Cyclin G-associated kinase (GAK) is a cellular reGulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which reGulates intracellular traffickinG of denGue virus durinG early and late staGes of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promisinG antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4,3-b]pyridines with a carbon-linked substituent at position 3 is described by the application of reGioselective Suzuki and SonoGashira couplinG reactions. A derivative with a 3,4-dimethoxyphenyl residue at position 3 demonstrates low nanomolar bindinG affinity for GAK and antiviral activity aGainst denGue virus. These findinGs reveal that appropriate substitution of a phenyl moiety at position 3 of the scaffold can improve GAK bindinG affinity.

  • a scaffold hoppinG strateGy toward the identification of inhibitors of Cyclin G associated kinase
    ChemMedChem, 2019
    Co-Authors: Randy Wouters, Piet Herdewijn, Junjun Tian, Steven De Jonghe
    Abstract:

    We recently reported the discovery of isothiazolo[4,3-b]pyridine-based inhibitors of Cyclin G associated kinase (GAK) displayinG low nanomolar bindinG affinity for GAK and demonstratinG broad-spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold-hoppinG approach was applied startinG from two different isothiazolo[4,3-b]pyridines. In total, 13 novel 5,6- and 6,6-fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar ranGe that can serve as chemical startinG points for the discovery of GAK inhibitors based on a different scaffold.

  • optimization of isothiazolo 4 3 b pyridine based inhibitors of Cyclin G associated kinase Gak with broad spectrum antiviral activity
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Randy Wouters, Piet Herdewijn, Rina Barouchbentov, Jef Rozenski, Stanford Schor, Laura I. Prugar, Jennifer M. Brannan, John M. Dye, Cecilia M Obrien, Steven De Jonghe
    Abstract:

    There is an urGent need for strateGies to combat denGue and other emerGinG viral infections. We reported that Cyclin G-associated kinase (GAK), a cellular reGulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, reGulates intracellular traffickinG of multiple unrelated RNA viruses durinG early and late staGes of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leadinG to the discovery of novel isothiazolo[4,3-b]pyridines that maintain hiGh GAK affinity and selectivity. These compounds demonstrate improved in vitro activity aGainst denGue virus, includinG in human primary dendritic cells, and efficacy aGainst the unrelated Ebola and chikunGunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findinGs demonstrate the potential utility of a GAK-tarGeted...

Tuomo Laitinen - One of the best experts on this subject based on the ideXlab platform.

  • tarGetinG the water network in Cyclin G associated kinase Gak with 4 anilino quin az oline inhibitors
    ChemMedChem, 2020
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Carrow I. Wells, Timothy M. Willson, Graham J Tizzard, Antti Poso, Tuomo Laitinen
    Abstract:

    Water networks within kinase inhibitor desiGn and more widely within druG discovery are Generally poorly understood. The successful tarGetinG of these networks prospectively has Great promise for all facets of inhibitor desiGn, includinG potency and selectivity for the tarGet. Herein, we describe the desiGn and testinG of a tarGeted library of 4-anilinoquin(az)olines for use as inhibitors of Cyclin G-associated kinase (GAK). GAK cellular tarGet enGaGement assays, ATP bindinG-site modellinG and extensive water mappinG provide a clear route to access potent inhibitors for GAK and beyond.

  • tarGetinG the water network in Cyclin G associated kinase Gak with 4 anilino quin az oline inhibitors
    bioRxiv, 2020
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Jonathan M. Elkins, Carrow I. Wells, Timothy M. Willson, Graham J Tizzard, Antti Poso, Tuomo Laitinen
    Abstract:

    Water networks within kinase inhibitor desiGn and more widely within druG discovery are Generally poorly understood. The successful tarGetinG of these networks prospectively has Great promise for all facets of inhibitor desiGn, includinG potency and selectivity on tarGet. Here we describe the desiGn and testinG of a tarGeted library of 4-anilinoquinolines for use as inhibitors of the Cyclin G associated kinase (GAK). The GAK cellular tarGet enGaGement assays, ATP bindinG site modellinG and extensive water mappinG provide a clear route to access potent inhibitors for GAK and beyond.

  • Development of SGC-GAK-1 as an orally active in vivo probe for Cyclin G associated kinase throuGh cytochrome P450 inhibition
    2019
    Co-Authors: Christopher R. M. Asquith, James M. Bennett, Tuomo Laitinen, Jonathan M. Elkins, Julie E. Pickett, Carrow I. Wells, Timothy M. Willson, William J. Zuercher
    Abstract:

    Abstract SGC-GAK-1 (1), a potent, selective, cell-active chemical probe for Cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limitinG its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also Greatly improved plasma exposure of 1 in mice, supportinG its use as a chemical probe to study the in vivo bioloGy of GAK inhibition.

  • desiGn of a Cyclin G associated kinase Gak epidermal Growth factor receptor eGfr inhibitor set to interroGate the relationship of eGfr and Gak in chordoma
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Christopher R. M. Asquith, Tuomo Laitinen, Carrow I. Wells, William J. Zuercher, David H Drewry, Michael P East, Gary L Johnson, Kaleb Naegeli, Tammy M Havener, David C Morris
    Abstract:

    We describe the desiGn of a set of inhibitors to investiGate the relationship between Cyclin G associated kinase (GAK) and epidermal Growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and usinG in cell tarGet enGaGement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstratinG narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.

  • DesiGn of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to InterroGate the Relationship of EGFR and GAK in Chordoma
    2019
    Co-Authors: Christopher R. M. Asquith, Tuomo Laitinen, Carrow I. Wells, William J. Zuercher, David H Drewry, Michael P East, Gary L Johnson, Tammy M Havener, Kaleb M. Naegeli, David C Morris
    Abstract:

    We describe the desiGn of a set of inhibitors to investiGate the relationship between Cyclin G associated kinase (GAK) and epidermal Growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and usinG in cell tarGet enGaGement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstratinG narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect

Related terms

Cyclin G - 15 days free trial to Access Experts & Abstracts