# Development of the HC2099 series of MmpL3 inhibitors to treat tuberculosis

> **NIH NIH R41** · TARN BIOSCIENCES, INC. · 2024 · $293,238

## Abstract

Tarn Biosciences, Inc. is a start-up pharmaceutical company headquartered in East Lansing, Michigan. The
company is developing new therapies for tuberculosis (TB). The goal of this STTR is to develop the MmpL3
inhibitor, HC2099, as a new treatment for drug susceptible and multidrug-resistant TB (MDR-TB). In 2019, 10
million people worldwide fell ill to TB with ~ 1.4 million lives lost. Standard-of-care (SOC) treatment for TB calls
for a protracted 6-month course of combination therapy to in which 14-24% of patients are nonadherent to
therapy. This long duration of treatment, high pill burden, and associated adverse drug effects, dramatically
impacts patient compliance and the evolution and spread of MDR-TB, with ~500,000 new MDR-TB infections
in 2019. Given that resistance to SOC treatment is as high as 10% in many countries, new drug regimens, with
new agents are required for slowing the spread of drug resistance.
 Mycobacterium tuberculosis (Mtb) is a remarkably successful, in part, due to the complex cell envelope that
surrounds the bacterium. MmpL3 is a mycolate flippase that moves the glycolipid trehalose monomycolate
(TMM) to the pseudoperiplasmic space, from where TMM is modified to trehalose dimycolate (TDM) and
incorporated into the mycomembrane. Mtb and M. smegmatis mmpL3 knockdown strains show that mmpL3 is
essential for survival both in vitro and in mice. Multiple MmpL3 inhibitors also exhibit synergistic interactions with
TB antibiotics, further supporting interest in this target.
 Using an innovative combination of untargeted and targeted mutant screens, we have identified ten new and
distinct scaffolds that inhibit MmpL3 function. One of these compounds, HC2099, was chosen for optimization
and characterization studies given observed properties usually regarded useful for drugs, including high aqueous
solubility and stability in microsomes. Structure-activity-relationship studies including the synthesis of >60
analogs resulted in >70-fold improvement of potency. Pilot studies show one of the optimized analogs, MSU-
43085, accumulates in mouse plasma and lungs and reduces Mtb growth in vivo when orally delivered.
 The product of this STTR is HC2099 analogs, a new series of MmpL3 inhibitors. HC2099 analogs are potent
(~100 nM EC50), soluble, orally bioavailable inhibitors targeting a pathway essential for Mtb survival. The goal of
this Phase I project is to prioritize three HC2099 analogs with favorable in vitro and in vivo drug-like properties
and demonstrate efficacy in chronically infected mice. Medicinal chemistry optimizations of HC2099 series will
be conducted to develop improved analogs (Aim 1.1) and in vitro drug-like properties will be characterized to
bias development towards a drug-like molecules (Aim 1.2). To drive towards proof-of-concept efficacy in vivo,
formulation studies (Aim 2.1), PK studies (Aim 2.2) and in vivo efficacy studies will be conducted in two models
of murine TB infection (Aim 2.3). The expected outcome ...

## Key facts

- **NIH application ID:** 10883595
- **Project number:** 5R41AI167105-02
- **Recipient organization:** TARN BIOSCIENCES, INC.
- **Principal Investigator:** John James Vrbanac
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $293,238
- **Award type:** 5
- **Project period:** 2023-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883595

## Citation

> US National Institutes of Health, RePORTER application 10883595, Development of the HC2099 series of MmpL3 inhibitors to treat tuberculosis (5R41AI167105-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883595. Licensed CC0.

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