Structure-guided discovery of cyclin-dependent kinase
inhibitors

J 2008

Structure-guided discovery of cyclin-dependent kinase inhibitors

FISCHMANN, Thierry, Alan HRUZA, Jose DUCA, Lata RAMANATHAN, Todd MAYHOOD et. al.

Základní údaje

Originální název

Structure-guided discovery of cyclin-dependent kinase inhibitors

Název česky

Structure-guided discovery of cyclin-dependent kinase inhibitors

Autoři

FISCHMANN, Thierry (840 Spojené státy), Alan HRUZA (840 Spojené státy), Jose DUCA (840 Spojené státy), Lata RAMANATHAN (840 Spojené státy), Todd MAYHOOD (840 Spojené státy), William WINDSOR (840 Spojené státy), Hung LE (840 Spojené státy), Timothy GUZI (840 Spojené státy), Michael DWYER (840 Spojené státy), Kamil PARUCH (203 Česká republika, garant), Ronald DOLL (840 Spojené státy), Emma LEES (840 Spojené státy), David PARRY (840 Spojené státy), Wolfgang SEGHEZZI (840 Spojené státy) a Vincent MADISON (840 Spojené státy)

Vydání

Biopolymers, 2008, 0006-3525

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10401 Organic chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 2.823

Kód RIV

RIV/00216224:14310/08:00035899

Organizační jednotka

Přírodovědecká fakulta

UT WoS

000254569700008

Klíčová slova česky

CDK2; kináza; inhibitor

Klíčová slova anglicky

CDK2; kinase; inhibitor

Štítky

CDK2, inhibitor, Kinase

Změněno: 25. 6. 2009 16:11, doc. Mgr. Kamil Paruch, Ph.D.

Anotace

ORIG CZ

V originále

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.

Česky

viz anotace

Citovat

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 a Vincent MADISON. Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers. 2008, roč. 2008, č. 89, s. 372-379. ISSN 0006-3525.

@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 a Vincent MADISON. Structure-guided discovery of cyclin-dependent kinase inhibitors. \textit{Biopolymers}. 2008, roč.~2008, č.~89, s.~372-379. ISSN~0006-3525.

Podrobný výpis o publikaci