Discovery of pyrazolopyridones as a novel class of gyrase B inhibitors using structure guided design

DOI: 10.1021/acsmedchemlett.5b00368

Authors: Jason B. Cross (Cubist Pharmaceuticals, Inc) , Jing Zhang (Cubist Pharmaceuticals, Inc) , Qingyi Yang (Cubist Pharmaceuticals, Inc) , Michael F. Mesleh (Cubist Pharmaceuticals, Inc) , Jan Antoinette C. Romero (Cubist Pharmaceuticals, Inc) , Bin Wang (Cubist Pharmaceuticals, Inc) , Doug Bevan (Cubist Pharmaceuticals, Inc) , Katherine M. Poutsiaka (Cubist Pharmaceuticals, Inc) , Felix Epie (Cubist Pharmaceuticals, Inc) , Terence Moy (Cubist Pharmaceuticals, Inc) , Anu Daniel (Cubist Pharmaceuticals, Inc) , Joseph Shotwell (Cubist Pharmaceuticals, Inc) , Brian Chamberlain (Cubist Pharmaceuticals, Inc) , Nicole Carter (Cubist Pharmaceuticals, Inc) , Ole Andersen (Evotec U.K., Ltd) , John Barker (Evotec U.K., Ltd) , M. Dominic Ryan (Cubist Pharmaceuticals, Inc) , Chester A. Metcalf (Cubist Pharmaceuticals, Inc) , Jared Silverman (Cubist Pharmaceuticals, Inc) , Kien Nguyen (Cubist Pharmaceuticals, Inc) , Blaise Lippa (Cubist Pharmaceuticals, Inc) , Roland E. Dolle (Cubist Pharmaceuticals, Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: February 2016

Abstract: The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens

Journal Keywords: Antibacterials; DNA gyrase B; fragment-based drug design; structure-based drug design

Diamond Keywords: Bacteria

Subject Areas: Medicine, Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 22/02/2016 12:32

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)