Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.
The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.
Trius Therapeutics, 6310 Nancy Ridge Dr., San Diego, CA 92121, USA. ltari@triusrx.com
Leslie W
LW
Tari
Michael
M
Trzoss
Daniel C
DC
Bensen
Xiaoming
X
Li
Zhiyong
Z
Chen
Thanh
T
Lam
Junhu
J
Zhang
Christopher J
CJ
Creighton
Mark L
ML
Cunningham
Bryan
B
Kwan
Mark
M
Stidham
Karen J
KJ
Shaw
Felice C
FC
Lightstone
Sergio E
SE
Wong
Toan B
TB
Nguyen
Jay
J
Nix
John
J
Finn
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D011743:Pyrimidines; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors; C527741:pyrrolopyrimidine; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase