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

  • Sci Rep. 2019 Nov 11;9(1):16452. doi: 10.1038/s41598-019-52795-1.
Gerson S Profeta  1  2 ,  Caio V Dos Reis  1  2 ,  André da S Santiago  1  2 ,  Paulo H C Godoi  1  2 ,  Angela M Fala  1  2 ,  Carrow I Wells  3 ,  Roger Sartori  2 ,  Anita P T Salmazo  2 ,  Priscila Z Ramos  1  2 ,  Katlin B Massirer  1  2 ,  Jonathan M Elkins  2  4 ,  David H Drewry  3 ,  Opher Gileadi  4 ,  Rafael M Couñago  5  6
Affiliations
  • 1. Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, 13083-875, Brazil.
  • 2. Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP, 13083-886, Brazil.
  • 3. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4. Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • 5. Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, 13083-875, Brazil. [email protected].
  • 6. Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP, 13083-886, Brazil. [email protected].
PMID: 31712618 DOI: 10.1038/s41598-019-52795-1
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.