Forge Therapeutics, Evotec launch platform to discover metalloenzyme inhibitors

Less than a year after forming a strategic alliance to develop novel antibiotics against some drug-resistant superbugs, Forge Therapeutics and Evotec have expanded their partnership on a discovery platform targeting metalloenzymes.

Different from the traditional hit discovery process which uses high-throughput screenings, this platform starts with metal-ligand interactions to identify metal-binding pharmacophore (MBP) fragments based on Forge’s library of more than 500 MBPs, Forge’s COO David Puerta explained in a release. “Using bioinorganic and medicinal chemistry principles, Forge transforms these MBP fragments into therapeutic leads using a novel fragment growth strategy incorporating our computational chemistry and structural biology,” he said.

The two teamed up last December to advance a novel antibiotic program targeting LpxC, a zinc metalloenzyme target long sought after for potential bacterial infection treatments, but which has seen little progress because of a lack of suitable chemical starting points. Forge applied its proprietary MBP library to identify potent druggable inhibitors of LpxC, while the CRO contributed its know-how in biochemistry, medicinal chemistry, structural biology, pharmacokinetics and program management.

Back in June, the pair presented the first efficacy data for their LpxC inhibitor in a mouse model. Researchers found that the novel antibiotic has comparable efficacy to ciprofloxacin in treating urinary tract infections, with significant burden reductions in both the bladder and kidney. Moreover, it also demonstrated in vitro potency against the notorious superbug E.coli, which is at the center of the recent antibiotic resistance crisis.

Now, with the initial success of that project, Forge and Evotec has decided to apply that same discovery strategy into this platform dubbed Blacksmith, aiming to develop a broader range of therapeutics focused on metalloenzymes.

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The initial focus of the platform will still be on infectious diseases. The biotech said it has performed over 50 metalloenzyme screens with hit rate of over 15%, giving them multiple starting points to develop new inhibitors.

A JLABS San Diego resident, Forge in March received one of the first research awards from the Combating Antibiotic Resistant Bacteria Accelerator (CARB-X), a public-private partnership established in August 2016 by HHS’ Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases in collaboration with the Wellcome Trust. To help advance its LpxC program, Forge gets an initial $4.8 million over 15 months and potentially $4 million more as milestone payments.

In April, it also pulled off a $15 million series A led by MagnaSci Ventures, and Evotec, among others, also participated. Company CEO Zachary Zimmerman, Ph.D., said at the time that the financing round, combined with the CARB-X grant, will support the lead LpxC program into clinical studies.