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PDBsum entry 4x7q
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Transferase/transferase inhibitor
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PDB id
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4x7q
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of low-Nanomolar pim kinase inhibitors.
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Authors
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A.Ishchenko,
L.Zhang,
J.Y.Le brazidec,
J.Fan,
J.H.Chong,
A.Hingway,
A.Raditsis,
L.Singh,
B.Elenbaas,
V.S.Hong,
D.Marcotte,
L.Silvian,
I.Enyedy,
J.Chao.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
474-480.
[DOI no: ]
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PubMed id
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Abstract
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PIM kinases are implicated in variety of cancers by promoting cell survival and
proliferation and are targets of interest for therapeutic intervention. We have
identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using
structure based modeling. The crystal structure of this compound with PIM1
confirmed the predicted binding mode and protein-ligand interactions except
those in the acidic ribose pocket. We show the SAR suggesting the importance of
having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this
interaction is not important for inhibiting PIM1 or PIM3. In addition, we report
the discovery of a new class of PIM inhibitors by using computational de novo
design tool implemented in MOE software (Chemical Computing Group). These
inhibitors have a different interaction profile.
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