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PDBsum entry 4zlo
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Transferase/transferase inhibitor
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PDB id
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4zlo
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References listed in PDB file
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Key reference
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Title
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Optimization of a dibenzodiazepine hit to a potent and selective allosteric pak1 inhibitor.
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Authors
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A.S.Karpov,
P.Amiri,
C.Bellamacina,
M.H.Bellance,
W.Breitenstein,
D.Daniel,
R.Denay,
D.Fabbro,
C.Fernandez,
I.Galuba,
S.Guerro-Lagasse,
S.Gutmann,
L.Hinh,
W.Jahnke,
J.Klopp,
A.Lai,
M.K.Lindvall,
S.Ma,
H.Möbitz,
S.Pecchi,
G.Rummel,
K.Shoemaker,
J.Trappe,
C.Voliva,
S.W.Cowan-Jacob,
A.L.Marzinzik.
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Ref.
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Acs Med Chem Lett, 2015,
6,
776-781.
[DOI no: ]
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PubMed id
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Abstract
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The discovery of inhibitors targeting novel allosteric kinase sites is very
challenging. Such compounds, however, once identified could offer exquisite
levels of selectivity across the kinome. Herein we report our structure-based
optimization strategy of a dibenzodiazepine hit 1, discovered in a
fragment-based screen, yielding highly potent and selective inhibitors of PAK1
such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to
an allosteric site and to reveal novel key interactions. Compound 3 modulated
PAK1 at the cellular level and due to its selectivity enabled valuable research
to interrogate biological functions of the PAK1 kinase.
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