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PDBsum entry 2wip
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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 n,1,4,4-Tetramethyl-8-{[4-(4-Methylpiperazin-1-Yl)phenyl]amino}-4,5-Dihydro-1h-Pyrazolo[4,3-H]quinazoline-3-Carboxamide (pha-848125), A potent, Orally available cyclin dependent kinase inhibitor.
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Authors
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M.G.Brasca,
N.Amboldi,
D.Ballinari,
A.Cameron,
E.Casale,
G.Cervi,
M.Colombo,
F.Colotta,
V.Croci,
R.D'Alessio,
F.Fiorentini,
A.Isacchi,
C.Mercurio,
W.Moretti,
A.Panzeri,
W.Pastori,
P.Pevarello,
F.Quartieri,
F.Roletto,
G.Traquandi,
P.Vianello,
A.Vulpetti,
M.Ciomei.
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Ref.
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J Med Chem, 2009,
52,
5152-5163.
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PubMed id
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Abstract
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The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs)
is described. Starting from compound 1, showing good potency as inhibitor of
CDKs but being poorly selective against a panel of serine-threonine and tyrosine
kinases, new analogues were synthesized. Enhancement in selectivity,
antiproliferative activity against A2780 human ovarian carcinoma cells, and
optimization of the physical properties and pharmacokinetic profile led to the
identification of highly potent and orally available compounds. Compound 28
(PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma
model showed good efficacy and was well tolerated upon repeated daily
treatments, was identified as a drug candidate for further development. Compound
28 is currently undergoing phase I and phase II clinical trials.
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