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PDBsum entry 3kb7
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References listed in PDB file
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Key reference
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Title
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Identification of 4,5-Dihydro-1h-Pyrazolo[4,3-H]quinazoline derivatives as a new class of orally and selective polo-Like kinase 1 inhibitors.
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Authors
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I.Beria,
D.Ballinari,
J.A.Bertrand,
D.Borghi,
R.T.Bossi,
M.G.Brasca,
P.Cappella,
M.Caruso,
W.Ceccarelli,
A.Ciavolella,
C.Cristiani,
V.Croci,
A.De ponti,
G.Fachin,
R.D.Ferguson,
J.Lansen,
J.K.Moll,
E.Pesenti,
H.Posteri,
R.Perego,
M.Rocchetti,
P.Storici,
D.Volpi,
B.Valsasina.
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Ref.
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J Med Chem, 2010,
53,
3532-3551.
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PubMed id
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Abstract
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Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression
whose overexpression is often associated with oncogenesis and therefore is
recognized as an attractive therapeutic target in the treatment of proliferative
diseases. Here we discuss the structure-activity relationship of the
4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a
high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase.
Furthermore, we describe the discovery of 49,
8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide,
as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007
microM) as well as its crystal structure in complex with the methylated
Plk1(36-345) construct. Compound 49 was active in cell proliferation against
different tumor cell lines with IC(50) values in the submicromolar range and
active in vivo in the HCT116 xenograft model where it showed 82% tumor growth
inhibition after repeated oral administration.
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