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Title: Structure-guided discovery of cyclin-dependent kinase inhibitors

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. (SPRI)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006794
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biopolymers; Journal Volume: 89; Journal Issue: (5) ; 05, 2008
Country of Publication:
United States
Language:
ENGLISH
Subject:
08 HYDROGEN; ATP; CRYSTAL STRUCTURE; HYDROGEN; INHIBITION; PHOSPHOTRANSFERASES; RESIDUES; WATER

Citation Formats

Fischmann, Thierry O., Hruza, Alan, Duca, Jose S., Ramanathan, Lata, Mayhood, Todd, Windsor, William T., Le, Hung V., Guzi, Timothy J., Dwyer, Michael P., Paruch, Kamil, Doll, Ronald J., Lees, Emma, Parry, David, Seghezzi, Wolfgang, and Madison, Vincent. Structure-guided discovery of cyclin-dependent kinase inhibitors. United States: N. p., 2008. Web. doi:10.1002/bip.20868.
Fischmann, Thierry O., Hruza, Alan, Duca, Jose S., Ramanathan, Lata, Mayhood, Todd, Windsor, William T., Le, Hung V., Guzi, Timothy J., Dwyer, Michael P., Paruch, Kamil, Doll, Ronald J., Lees, Emma, Parry, David, Seghezzi, Wolfgang, & Madison, Vincent. Structure-guided discovery of cyclin-dependent kinase inhibitors. United States. doi:10.1002/bip.20868.
Fischmann, Thierry O., Hruza, Alan, Duca, Jose S., Ramanathan, Lata, Mayhood, Todd, Windsor, William T., Le, Hung V., Guzi, Timothy J., Dwyer, Michael P., Paruch, Kamil, Doll, Ronald J., Lees, Emma, Parry, David, Seghezzi, Wolfgang, and Madison, Vincent. Thu . "Structure-guided discovery of cyclin-dependent kinase inhibitors". United States. doi:10.1002/bip.20868.
@article{osti_1006794,
title = {Structure-guided discovery of cyclin-dependent kinase inhibitors},
author = {Fischmann, Thierry O. and Hruza, Alan and Duca, Jose S. and Ramanathan, Lata and Mayhood, Todd and Windsor, William T. and Le, Hung V. and Guzi, Timothy J. and Dwyer, Michael P. and Paruch, Kamil and Doll, Ronald J. and Lees, Emma and Parry, David and Seghezzi, Wolfgang and Madison, Vincent},
abstractNote = {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.},
doi = {10.1002/bip.20868},
journal = {Biopolymers},
number = (5) ; 05, 2008,
volume = 89,
place = {United States},
year = {Thu Oct 02 00:00:00 EDT 2008},
month = {Thu Oct 02 00:00:00 EDT 2008}
}