| FISCHMANN, Thierry, Alan HRUZA, Jose DUCA, Lata RAMANATHAN, Todd MAYHOOD, William WINDSOR, Hung LE, Timothy GUZI, Michael DWYER, Kamil PARUCH, Ronald DOLL, Emma LEES, David PARRY, Wolfgang SEGHEZZI and Vincent MADISON. Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers. 2008, vol. 2008, No 89, p. 372-379. ISSN 0006-3525. |
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@article{837935,
author = {Fischmann, Thierry and Hruza, Alan and Duca, Jose and Ramanathan, Lata and Mayhood, Todd and Windsor, William and Le, Hung and Guzi, Timothy and Dwyer, Michael and Paruch, Kamil and Doll, Ronald and Lees, Emma and Parry, David and Seghezzi, Wolfgang and Madison, Vincent},
article_number = {89},
keywords = {CDK2; kinase; inhibitor},
language = {eng},
issn = {0006-3525},
journal = {Biopolymers},
title = {Structure-guided discovery of cyclin-dependent kinase inhibitors},
volume = {2008},
year = {2008}
}
TY - JOUR
ID - 837935
AU - Fischmann, Thierry - Hruza, Alan - Duca, Jose - Ramanathan, Lata - Mayhood, Todd - Windsor, William - Le, Hung - Guzi, Timothy - Dwyer, Michael - Paruch, Kamil - Doll, Ronald - Lees, Emma - Parry, David - Seghezzi, Wolfgang - Madison, Vincent
PY - 2008
TI - Structure-guided discovery of cyclin-dependent kinase inhibitors
JF - Biopolymers
VL - 2008
IS - 89
SP - 372-379
EP - 372-379
SN - 00063525
KW - CDK2
KW - kinase
KW - inhibitor
N2 - CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.
ER -
FISCHMANN, Thierry, Alan HRUZA, Jose DUCA, Lata RAMANATHAN, Todd MAYHOOD, William WINDSOR, Hung LE, Timothy GUZI, Michael DWYER, Kamil PARUCH, Ronald DOLL, Emma LEES, David PARRY, Wolfgang SEGHEZZI and Vincent MADISON. Structure-guided discovery of cyclin-dependent kinase inhibitors. \textit{Biopolymers}. 2008, vol.~2008, No~89, p.~372-379. ISSN~0006-3525.
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