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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.

Original publication

DOI

10.1021/jm0504858

Type

Journal article

Journal

J Med Chem

Publication Date

01/12/2005

Volume

48

Pages

7604 - 7614

Keywords

Antineoplastic Agents, Crystallization, Crystallography, X-Ray, Flavonoids, Humans, Imidazoles, Indoles, Maleimides, Models, Molecular, Molecular Structure, Moloney murine leukemia virus, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-pim-1, Proviruses, Pyrazoles, Pyridazines, Pyrimidines, Structure-Activity Relationship