# Preclinical Development of the TAK1 Inhibitor HS-276 for the Treatment of Rheumatoid Arthritis

> **NIH NIH R44** · EYDIS BIO, INC. · 2021 · $796,786

## Abstract

PROJECT SUMMARY / ABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which hyperactivated immune cells induce
maladaptive persistent inflammation in the joints, leading to synovial inflammation and bone remodeling. In the
US, RA currently affects roughly 1% of the population and carries a total annual societal cost burden of
approximately $39.2 billion. In RA, sustained elevations of pro-inflammatory cytokines elicit chronic tissue
damage and pain, which ultimately leads to loss of mobility and significant impairment of the patient’s lifestyle.
Tumor necrosis factor (TNF) has been shown to play an important role in RA pathogenesis and pro-inflammatory
signaling, and various TNF-sequestering antibodies (e.g., Remicade® and Enbrel®) are indicated for this disease.
However, up to 40% of patients fail to respond to these therapies, treatments are burdened with high
administration costs and noncompliance rates, and almost all carry serious safety issues, leading to a large need
for an orally bioavailable alternative with a novel MOA which can modulate the intracellular effects of TNF and
mitigate RA symptoms and damage. A key signaling element in the mediated TNF pro-survival/inflammatory
response pathway is the protein kinase TGFβ-activated protein kinase 1 (TAK1). TAK1 plays a crucial role in
facilitating activation of protein kinase-mediated signaling pathways implicated in the pathogenesis of
inflammatory and oncogenic processes. Because of its critical role in these pathways, TAK1 has emerged as a
potential therapeutic target for the treatment of various inflammatory-mediated diseases, including RA. Our
recent discovery of the takinib scaffold and subsequent medicinal chemistry efforts have led to the development
of an orally bioavailable, highly selective and potent (IC50 ~2.5nM) inhibitor of TAK1, HS-276. This lead candidate
has demonstrated promising results from preliminary efficacy and pharmacokinetic studies which support
targeted inhibitor of TAK1 as a valid approach to regulating TNF production and signaling. Additionally, since the
role of TAK1 appears to be largely confined to mediating TNF signaling, such an orally bioavailable drug should
potentially have limited side effects, in contrast to current targeted RA therapeutics. In order to progress HS-276
towards IND-enabling safety studies, this project involves the following Specific Aims: Aim 1: Establish safety
and chemical toxicology of HS-276 in pre-IND-enabling studies. Milestone: Establish route of metabolism,
maximum tolerated doses, and define unexpected toxicity issues. Aim 2: Define the therapeutic window for HS-
276 in the CIA mouse model of human RA. Determination of therapeutic window, demonstration of in vivo target
engagement and characterization of biomarkers of efficacy. Milestone: Therapeutic window fully defined. Aim 3:
Develop a backup series of analogs showing oral bioavailability and increased potency. Milestone: Identify
backup analogs in the...

## Key facts

- **NIH application ID:** 10259629
- **Project number:** 2R44AR076772-02A1
- **Recipient organization:** EYDIS BIO, INC.
- **Principal Investigator:** TIMOTHY A HAYSTEAD
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $796,786
- **Award type:** 2
- **Project period:** 2021-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259629

## Citation

> US National Institutes of Health, RePORTER application 10259629, Preclinical Development of the TAK1 Inhibitor HS-276 for the Treatment of Rheumatoid Arthritis (2R44AR076772-02A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10259629. Licensed CC0.

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