Non-hydroxamate LpxC inhibitors
A Vernalis and Taisho collaboration designed around the hydroxamate zinc-binding group, delivering an antibacterial lead active against Pseudomonas aeruginosa.
The Challenge
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyses the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety, raising concerns about binding to other metalloenzymes.
The Science
A collaboration between Vernalis Research and Taisho Pharmaceuticals used fragment and structure-based methods for the discovery and optimisation of two series of compounds with differing modes of zinc coordination.
One series was evolved from a fragment in which a glycine moiety complexes zinc. It achieved low nanomolar potency in an enzyme functional assay, but poor antibacterial activity in cell cultures.
A second series was based on a fragment that coordinated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative, compound 43, exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 ug/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.
Crystal structure of compound 43 bound to the active site of PaLpxC, showing zinc coordination to the ligand and protein side chains.
Key Takeaways
- Two compound series developed with differing zinc coordination, avoiding the hydroxamate liability
- Compound 43 combines low nanomolar LpxC inhibition with an MIC of 4 ug/mL against P. aeruginosa
- Activity little affected by albumin — a practical developability signal
- The only anti-infective programme in the Vernalis case study portfolio
Service Areas
Work with us
Vernalis has collaborated with a wide range of partners to enable some of the most challenging therapeutic targets. Present and past collaborators include Servier, Pierre Fabre, Genentech and Lundbeck. Vernalis can support programs with DEL and fragment-based technologies through to establishing full drug discovery programmes for our partners.
Our track record is built on innovation and success in enabling drug discovery and identifying clinical candidates for a wide variety of therapeutic targets.
Research Director and Joint Site Lead
James Murray PhD
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