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Aug 22, 2016
 |  BioCentury  |  Emerging Company Profile

Metal smithing

How Forge's metal-binding chemistry can tackle tough metalloenzyme targets

Forge Therapeutics Inc. is using a library of metal-binding pharmacophores that avoid known pharmacologic and safety liabilities of a common metal-binding motif to create inhibitors of metalloenzymes, starting with notoriously tough targets.

Forge's lead program is a broad-spectrum Gram-negative antibiotic targeting UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC).

Metalloenzymes play roles in many biologic processes including gene regulation, protein matrix degradation and antibiotic resistance. CEO Zachary Zimmerman said there are hundreds of metalloenzymes - enzymes that use metal in their active site - but a dearth of good starting chemical scaffolds to create safe and effective inhibitors.

The common metal-binding moiety is hydroxamic acid, which Zimmerman said binds and inhibits metalloenzymes well in vitro but is fraught with problems like promiscuity and mutagenicity when taken into animals. Hydroxamic acids tend to have poor bioavailability and are quickly recognized by serum enzymes that hydrolyze the moiety into products unable to bind the metal. "All of these compounds have poor pharmacokinetics, poor bioavailability, and to top it off, all the hydrolysis products are toxic,"...

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