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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Crystallization
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Crystallography, X-Ray
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Flavonoids / chemical synthesis
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Flavonoids / chemistry
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Indoles / chemical synthesis*
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Indoles / chemistry
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Maleimides / chemical synthesis*
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Maleimides / chemistry
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Models, Molecular
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Molecular Structure
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Moloney murine leukemia virus / enzymology
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Moloney murine leukemia virus / physiology*
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Phosphorylation
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Protein Binding
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / chemistry*
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Proviruses / physiology*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyridazines / chemical synthesis
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Pyridazines / chemistry
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Flavonoids
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Imidazoles
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Indoles
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Maleimides
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Pyrazoles
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Pyridazines
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Pyrimidines
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Proto-Oncogene Proteins c-pim-1
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bisindolylmaleimide