title: Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM-1) kinase.
abstract: The kinase PIM-1 plays a pivotal role in cytokine signaling and is implicated in the development of a number of tumors. The three-dimensional structure of PIM-1 is characterized by an unique hinge region which lacks a second hydrogen bond donor and makes it particularly important to determine how inhibitors bind to this kinase. We determined the structures of PIM-1 in complex with bisindolylmaleimide (BIM-1) and established the structure-activity relationship (SAR) for this inhibitor class. In addition, we screened a kinase targeted library and identified a number of high affinity inhibitors of PIM-1 such as imidazo[1,2-b]pyridazines, pyrazolo[1,5-a]pyrimidines, and members of the flavonoid family. In this paper we present an initial SAR of the identified scaffolds determined on the basis of a thermostability shift assay, calorimetric binding data, and biochemical assays which may find applications for the treatment of PIM-1 dependent cancer types.
authors.affiliation: Structural Genomics Consortium (SGC), Botnar Research Centre, Oxford University, Oxford OX3 7LD, UK. alex.bullock@sgc.ox.ac.uk
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Judit E
authors.initials: JE
authors.lastname: Debreczeni
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Fedorov
authors.forename: Adam
authors.initials: A
authors.lastname: Nelson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D008979:Moloney murine leukemia virus / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011533:Proviruses / Q000502:physiology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D011720:Pyrazoles; D011724:Pyridazines; D011743:Pyrimidines; D051573:Proto-Oncogene Proteins c-pim-1; C088060:bisindolylmaleimide