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PDBsum entry 2bpm
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References listed in PDB file
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Key reference
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Title
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3-Aminopyrazole inhibitors of cdk2/cyclin a as antitumor agents. 2. Lead optimization.
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Authors
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P.Pevarello,
M.G.Brasca,
P.Orsini,
G.Traquandi,
A.Longo,
M.Nesi,
F.Orzi,
C.Piutti,
P.Sansonna,
M.Varasi,
A.Cameron,
A.Vulpetti,
F.Roletto,
R.Alzani,
M.Ciomei,
C.Albanese,
W.Pastori,
A.Marsiglio,
E.Pesenti,
F.Fiorentini,
J.R.Bischoff,
C.Mercurio.
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Ref.
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J Med Chem, 2005,
48,
2944-2956.
[DOI no: ]
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PubMed id
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Abstract
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Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are
currently undergoing clinical trials to verify their potential as new anticancer
agents. In a previous article we described the lead discovery process of a
3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this
process was PNU-292137, a compound endowed with in vivo antitumor activity in a
mouse tumor xenograft model. We optimized this lead compound to improve some
physicochemical properties, notably solubility and plasma protein binding. This
lead optimization process brought us to the discovery of
(2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide
(PHA-533533, 13), a compound with a balanced activity vs druglike profile.
Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor
cell proliferation of different cell lines with an IC(50) in the submicromolar
range. Solubility was improved more than 10 times over the starting lead, while
plasma protein binding was decreased from 99% to 74%. With exploitation of this
globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo
in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of
mechanism of action was obtained in vivo by immunohistochemical analysis of
tumor slices of 13-treated vs untreated animals.
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