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PDBsum entry 4o2p
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Transferase/transferase inhibitor
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PDB id
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4o2p
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References listed in PDB file
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Key reference
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Title
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Combining X-Ray crystallography and molecular modeling toward the optimization of pyrazolo[3,4-D]pyrimidines as potent c-Src inhibitors active in vivo against neuroblastoma.
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Authors
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C.Tintori,
A.L.Fallacara,
M.Radi,
C.Zamperini,
E.Dreassi,
E.Crespan,
G.Maga,
S.Schenone,
F.Musumeci,
C.Brullo,
A.Richters,
F.Gasparrini,
A.Angelucci,
C.Festuccia,
S.Delle monache,
D.Rauh,
M.Botta.
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Ref.
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J Med Chem, 2015,
58,
347-361.
[DOI no: ]
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PubMed id
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Abstract
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c-Src is a tyrosine kinase belonging to the Src-family kinases. It is
overexpressed and/or hyperactivated in a variety of cancer cells, thus its
inhibition has been predicted to have therapeutic effects in solid tumors.
Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl
inhibitor. Herein we describe a multidisciplinary drug discovery approach for
the optimization of the lead 3 against c-Src. Starting from the X-ray crystal
structure of c-Src in complex with 3, Monte Carlo free energy perturbation
calculations were applied to guide the design of c-Src inhibitors with improved
activities. As a result, the introduction of a meta hydroxyl group on the C4
anilino ring was computed to be particularly favorable. The potency of the
synthesized inhibitors was increased with respect to the starting lead 3. The
best identified compounds were also found active in the inhibition of
neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo
activity in xenograft model using SH-SY5Y cells.
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