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PDBsum entry 7ajs
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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-Guided discovery of potent and selective dyrk1a inhibitors.
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Authors
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C.Weber,
M.Sipos,
A.Paczal,
B.Balint,
V.Kun,
N.Foloppe,
P.Dokurno,
A.J.Massey,
D.L.Walmsley,
R.E.Hubbard,
J.Murray,
K.Benwell,
T.Edmonds,
D.Demarles,
A.Bruno,
M.Burbridge,
F.Cruzalegui,
A.Kotschy.
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Ref.
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J Med Chem, 2021,
64,
6745-6764.
[DOI no: ]
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PubMed id
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Abstract
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The kinase DYRK1A is an attractive target for drug discovery programs due to its
implication in multiple diseases. Through a fragment screen, we identified a
simple biaryl compound that is bound to the DYRK1A ATP site with very high
efficiency, although with limited selectivity. Structure-guided optimization
cycles enabled us to convert this fragment hit into potent and selective DYRK1A
inhibitors. Exploiting the structural differences in DYRK1A and its close
homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors.
Our best compounds potently inhibited DYRK1A in the cell culture and in
vivo and demonstrated drug-like properties. The inhibition of DYRK1A in
vivo translated into dose-dependent tumor growth inhibition in a model of
ovarian carcinoma.
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