LpxC

SAN DIEGO, March 19, 2024 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, announced today that it will present a talk and poster highlighting its novel chemistry technology platform for metalloenzyme inhibitors of LpxC for the treatment of infections caused by multidrug-resistant Gram-negative bacteria at the New Antibacterial Discovery and Development Gordon Research Conference (GRC): Innovative Approaches in Antibacterial Research and Development to Fight the Antibiotic Resistance Crisis being held March 17-22, 2024, in Ventura, CA. "We are looking forward to attending the GRC and presenting an overview of Blacksmith's discovery platform along with a progress update on our novel class small-molecule antibacterial targeting LpxC," said Andrew Tomaras, Ph.D., Senior Vice President of Blacksmith. "Our lead candidate, currently undergoing IND-enabling studies, has demonstrated activity against susceptible and multidrug-resistant Gram-negative organisms included on the WHO and CDC bacterial threat lists, and is currently being pursued using both IV and oral routes of administration for indications such as UTI." Talk Presentation Details: Title: "Anti-Infective Candidates with Novel Targets Using the Blacksmith Discovery Platform" Category: Discovery Pipelines, Hits, Leads and Candidates Date and Time: Tuesday, March 19 at 11:05am – 11:25am Pacific Poster Presentation Details: Title: "Advanced preclinical in vitro and in vivo characterization of a novel, non-hydroxamate-based LpxC inhibitor for the intravenous and oral treatment of multidrug-resistant Enterobacterales" Date and Time: Thursday, March 21 at 4:00pm – 6:00pm Pacific Poster Board Number: 13 More information can be found on the meeting website at 2024 New Antibacterial Discovery and Development GRC and, following the presentation, a version of the poster will be made available on the Blacksmith Medicines website About LpxC LpxC, a zinc hydrolase, is an attractive and highly sought-after antibiotic target – it is conserved across Gram-negative bacteria and not found in Gram-positive bacteria or human cells. Inhibiting LpxC results in potent killing of Gram-negative bacteria with the benefit of sparing Gram-positive bacteria such as those residing in the protective microbiome of the gut which help to deter opportunistic C. difficile infections. Other LpxC inhibitors have been evaluated by biopharma in the past but chemistry limitations (e.g. hydroxamic acid) have yielded ineffective compounds that suffer from poor drug-like properties. Thus, there are no approved therapeutics targeting LpxC. Blacksmith, using its proprietary chemistry platform, has developed novel non-hydroxamate inhibitors of LpxC that are safe and effective in animal models of Gram-negative infection and are able to kill Gram-negative 'superbugs' where other antibiotics are ineffective. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn. Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines

SAN DIEGO, Feb. 21, 2024 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, announced today the release of $3.3M from its contract with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), Department of Health and Human Services (HHS), to conduct IND-enabling and Phase 1 studies of FG-2101, its novel non-hydroxamate LpxC inhibitor, using both intravenous (IV) and oral administration for the treatment of urinary tract infections caused by multidrug-resistant Gram-negative bacteria. The company's recent successful completion of certain Base Period activities including preclinical toxicology studies triggered the release of this award under its contract with NIAID (75N93022C00060). The total funding could be up to $17.2M over five years, depending on contract options exercised. The new funding will be used for GMP clinical material manufacturing and IND preparation/submission. "With support from NIAID, we have successfully completed preclinical toxicology studies including 7-day and 14-day repeat dose assessments (non-GLP and GLP) and safety pharmacology evaluations including cardiovascular, respiratory and CNS assessments of our novel non-hydroxamate LpxC inhibitor FG-2101," said Andrew Tomaras, Ph.D., Senior Vice President of Blacksmith. "Next, with the achievement of these safety studies, we will initiate the preparation of an investigational new drug (IND) application as well as the manufacturing campaign of GMP material for upcoming clinical studies. We are extremely grateful to the NIAID team for their continued support for the candidacy of our potential first-in-class antibacterial agent." About LpxC LpxC, a zinc metalloenzyme, is an attractive and highly sought-after antibiotic target – it is conserved across Gram-negative bacteria and not found in Gram-positive bacteria or human cells. Inhibiting LpxC results in potent killing of Gram-negative bacteria with the presumed benefit of sparing Gram-positive bacteria such as those residing in the protective microbiome of the gut which help to deter opportunistic C. difficile infections. Other LpxC inhibitors have been evaluated by biopharma in the past but chemistry limitations (e.g. hydroxamic acid) have yielded ineffective compounds that suffer from poor drug-like properties. Thus, there are no approved therapeutics targeting LpxC. Blacksmith, using its proprietary chemistry platform, has developed novel non-hydroxamate inhibitors of LpxC that are safe and effective in animal models of Gram-negative infection and are able to kill Gram-negative 'superbugs' where other antibiotics are ineffective. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines

A scientific journey decades in the making has found a new antibiotic strategy to defeat gram-negative bacteria like Salmonella, Pseudomonas and E. coli, the culprits in many urinary tract infections. The synthetic molecule works fast and is durable. It interferes with synthesis of the bacterial outer membrane by jamming an enzyme. When tested against a clinical collection of 285 bacterial strains, including some that were highly resistant to commercial antibiotics, it killed them all. A scientific journey decades in the making at Duke University has found a new antibiotic strategy to defeat gram-negative bacteria like Salmonella, Pseudomonas and E. coli, the culprits in many urinary tract infections (UTIs). The synthetic molecule works fast and is durable in animal tests. It works by interfering with a bacterium's ability to make its outer lipid layer, its skin, so to speak. "If you disrupt the synthesis of the bacterial outer membrane, the bacteria cannot survive without it," said lead investigator Pei Zhou, a professor of biochemistry in the Duke School of Medicine. "Our compound is very good and very potent." The compound, called LPC-233, is a small molecule that has proven effective at wrecking the outer membrane lipid biosynthesis in every gram-negative bacterium it was tested against. Co-authors at the University of Lille in France tested it against a collection of 285 bacterial strains, including some that were highly resistant to commercial antibiotics, and it killed them all. And it works fast. "LPC-233 can reduce bacterial viability by 100,000-fold within four hours," Zhou said. The compound is also tenacious enough to survive all the way to the urinary tract after oral administration, which may make it a vital tool against stubborn urinary tract infections (UTIs). Tests run at high concentrations of the compound showed "exceedingly low rates of spontaneous resistance mutations in these bacteria," according to a paper describing the findings, which appears Aug. 9 in Science Translational Medicine. In animal studies, the compound was successful when administered orally and intravenously or injected into the abdomen. In one experiment, mice given what should have been a fatal dose of multidrug-resistant bacteria were rescued by the new compound. The search for this compound took decades because of the specificity and safety required of the synthetic molecule. Zhou credits his late colleague, former Duke Biochemistry Chair Christian Raetz, for starting the search decades ago. "He spent his entire career working on this pathway," Zhou said. "Dr. Raetz proposed a conceptual blueprint for this pathway in the 1980s, and it took him over two decades to identify all of the players," Zhou said. The new drug's target is an enzyme called LpxC that is the second enzyme in the "Raetz pathway" and is essential to making the outer membrane lipid in gram-negative bacteria. Raetz joined Duke as the chairman of biochemistry in 1993 after his work on this pathway at Merck & Co. had failed to produce a successful clinical candidate. The Merck antibiotic worked, but only against E. coli, so it wasn't commercially viable and the pharmaceutical company dropped it. "He actually recruited me to Duke to work on this enzyme, initially just from the structural biology perspective," said Zhou, who came to Duke in 2001. Zhou and Raetz had solved the structure of the LpxC enzyme and revealed molecular details of a few potential inhibitors. "We realized that we could tweak the compound to make it better," Zhou said. Since then, Zhou has been working with his colleague, Duke Chemistry professor Eric Toone, to make more potent LpxC inhibitors. The first human trial of LpxC inhibitors had failed because of cardiovascular toxicity. The focus of the Duke group's subsequent work was to avoid cardiovascular effects while maintaining the potency of the compound. They worked on more than 200 different versions of the enzyme inhibitor, always searching for better safety and more potency. Other compounds worked to varying degrees, but compound number 233 was the winner. LPC-233 fits a binding spot on the LpxC enzyme and prevents it from doing its work. "It fits in the right way to inhibit formation of the lipid," Zhou said. "We're jamming the system." Adding to its durability, the compound works by a remarkable two-step process, Zhou said. After the initial binding to LpxC, the enzyme-inhibitor complex changes its shape somewhat to become an even more stable complex. The lifetime of the inhibitor binding in this more stable complex is longer than the lifetime of the bacteria. "We think that contributes to the potency, as it has a semi-permanent effect on the enzyme," he said. "Even after the unbound drug is metabolized by the body, the enzyme is still inhibited due to the extremely slow inhibitor dissociation process," Zhou said. There are multiple patents being filed on the series of compounds, and Toone and Zhou have co-founded a company called Valanbio Therapeutics, Inc. which will be looking for partners to bring LPC-233 through phase 1 clinical trials to assess safety and efficacy in humans. "All of these studies were done in animals," Zhou said. "Ultimately the cardiovascular safety needs to be tested in humans." Large scale synthesis of LPC-233 was first accomplished by David Gooden at the Duke Small Molecule Synthesis Facility. Vance Fowler and Joshua Thaden (Duke School of Medicine), Ziqiang Guan (Biochemistry) and Ivan Spasojevic (Duke PK/PD Core) helped with in vivo studies, mass spectrometry and pharmacokinetics analysis. This work was supported by grants from National Institutes of Health (R01 GM115355, AI094475, AI152896, AI148366), the North Carolina Biotechnology Center (2016-TEG-1501) and a National Cancer Institute Comprehensive Cancer Center Core Grant (P30CA014236).