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

Author(s):Show less -

Profeta, Gerson S. ^{[1, 2]} ; dos Reis, Caio V. ^{[1, 2]} ; Santiago, Andre da S. ^{[1, 2]} ; Godoi, Paulo H. C. ^{[1, 2]} ; Fala, Angela M. ^{[1, 2]} ; Wells, Carrow I. ^[3] ; Sartori, Roger ^[1] ; Salmazo, Anita P. T. ^[1] ; Ramos, Priscila Z. ^{[1, 2]} ; Massirer, Katlin B. ^{[1, 2]} ; Elkins, Jonathan M. ^{[4, 1]} ; Drewry, David H. ^[3] ; Gileadi, Opher ^[4] ; Counago, Rafael M. ^{[1, 2]}

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolucao, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[2] Univ Estadual Campinas UNICAMP, CBMEG, Ctr Quim Med CQMED, BR-13083875 Campinas, SP - Brazil

^[3] Univ N Carolina, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 - USA

^[4] Univ Oxford, Struct Genom Consortium, Old Rd Campus Res Bldg, Roosevelt Dr, Oxford OX3 7DQ - England

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 9, NOV 11 2019.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 19/14275-8 - Structural analysis of the kinase proteins PRPF4 and DYRK1B, from the CMGC family, and identification of small compound inhibitors
• Grantee: André da Silva Santiago
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE