Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors.
Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is hig...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2019
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| _version_ | 1826256706909241344 |
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| author | Profeta, GS Reis, CVD Santiago, ADS Godoi, PHC Fala, AM Wells, CI Sartori, R Salmazo, APT Ramos, PZ Massirer, KB Elkins, JM Drewry, DH Gileadi, O Couñago, RM |
| author_facet | Profeta, GS Reis, CVD Santiago, ADS Godoi, PHC Fala, AM Wells, CI Sartori, R Salmazo, APT Ramos, PZ Massirer, KB Elkins, JM Drewry, DH Gileadi, O Couñago, RM |
| author_sort | Profeta, GS |
| collection | OXFORD |
| description | Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK. |
| first_indexed | 2024-03-06T18:06:30Z |
| format | Journal article |
| id | oxford-uuid:0198af17-2410-436b-8201-56c4dfde83a9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:06:30Z |
| publishDate | 2019 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:0198af17-2410-436b-8201-56c4dfde83a92022-03-26T08:35:56ZBinding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0198af17-2410-436b-8201-56c4dfde83a9EnglishSymplectic ElementsSpringer Nature2019Profeta, GSReis, CVDSantiago, ADSGodoi, PHCFala, AMWells, CISartori, RSalmazo, APTRamos, PZMassirer, KBElkins, JMDrewry, DHGileadi, OCouñago, RMCalcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK. |
| spellingShingle | Profeta, GS Reis, CVD Santiago, ADS Godoi, PHC Fala, AM Wells, CI Sartori, R Salmazo, APT Ramos, PZ Massirer, KB Elkins, JM Drewry, DH Gileadi, O Couñago, RM Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title | Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title_full | Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title_fullStr | Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title_full_unstemmed | Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title_short | Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. |
| title_sort | binding and structural analyses of potent inhibitors of the human ca2 calmodulin dependent protein kinase kinase 2 camkk2 identified from a collection of commercially available kinase inhibitors |
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