# IND-enabling studies of the potent LpxC inhibitor LPC-233 as a novel antibiotic against Gram-negative pathogens

> **NIH NIH R44** · VALANBIO THERAPEUTICS, INC. · 2021 · $794,342

## Abstract

Project Summary/Abstract
 The rapidly increasing incidences of infections caused by multidrug-resistant Gram-negative bacteria
represent an emerging global health care crisis. The fact that no new class of medication against Gram-
negative bacteria has been introduced into practice over half of a century, combined with the lengthy
development and approval process, add to the urgency to accelerate and streamline research and
development processes for new treatment approaches to Gram-negative bacterial infections.
 LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is an essential enzyme in the
biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide and the major lipid component of the
outer monolayer of the Gram-negative bacterial outer membrane. Constitutive lipid A biosynthesis is required
for bacterial viability and fitness in the human host. As such, LpxC is an attractive target to create a novel class
of small molecule inhibitors as antibacterial agents specific to Gram-negative bacterial pathogens. Extensive
research over the last two decades shows that (1) potent LpxC inhibitors display outstanding bactericidal
effect; (2) with few exceptions in vitro, virtually all Gram-negative bacteria are sensitive to LpxC inhibition in
vivo; and (3) LpxC inhibitors are not inactivated by common resistance mechanisms such as extended-
spectrum -lactamases (ESBL) or carbapenemases. Although dose-limiting adverse effects have limited the
development of the most advanced LpxC inhibitors, ACHN-975 (Achaogen) and RC-0 1 (Recida Therapeutics),
these compounds do not show the same liabilities, suggesting that the observed adverse effects do not
represent a class limitation.
 Valanbio Therapeutics was founded to translate basic research activities from Duke University into a
potential new class of antibacterial agents against Gram-negative pathogens. Duke University and Valanbio
Therapeutics have identified a lead LpxC inhibitor, LPC-233, which we seek to advance to the clinical stage
testing. LPC-233 is potently and broadly bactericidal against Gram-negative bacteria in vitro and significantly
reduces bacterial counts in the murine thigh infection model at doses as low as 2 mg/kg BID. It also displays
an outstanding safety profile in rats. In this proposal, Valanbio Therapeutics plans to (1) develop GMP-
compatible large-scale synthesis of LPC-233; (2) continue to evaluate and optimize the efficacy and dosing
regimen of LPC-233 against susceptible and multidrug-resistant Gram-negative bacterial pathogens in mice;
(3) investigate the potential dose-limiting safety liabilities in vitro and in vivo. The successful execution of the
proposed studies will clear the path for IND filing and advance LPC-233 to Phase I human clinical trials.

## Key facts

- **NIH application ID:** 10146290
- **Project number:** 5R44AI152896-02
- **Recipient organization:** VALANBIO THERAPEUTICS, INC.
- **Principal Investigator:** Clayton Duncan
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $794,342
- **Award type:** 5
- **Project period:** 2020-04-16 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146290

## Citation

> US National Institutes of Health, RePORTER application 10146290, IND-enabling studies of the potent LpxC inhibitor LPC-233 as a novel antibiotic against Gram-negative pathogens (5R44AI152896-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146290. Licensed CC0.

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