# Evaluating the Blood-Brain Barrier Bioavailability and in vivo Efficacy Potential of a Novel TAK1 Inhibitor Targeting Chronic Pain

> **NIH NIH R43** · EYDIS BIO, INC. · 2021 · $480,955

## Abstract

Project Summary / Abstract
Chronic pain is a prevalent health concern, affecting up to 100 million people and carrying an economic burden
up to $560 billion annually in the US alone, yet treatment options remain limited. Over-the-counter nonsteroidal
anti-inflammatory drugs (NSAIDs) are short-acting and fail to alleviate severe chronic pain, and these
conventional drugs carry serious safety concerns regarding gastrointestinal events. In addition, the newer and
more selective COX-2 inhibitors such as Celebrex®/celecoxib and Vioxx® carry FDA boxed warnings concerning
serious risks of heart attack and stroke. Similarly, longer-acting centrally-targeted therapies such as opioids also
have poor efficacy and produce serious side-effects regarding altered mental state, addiction, and respiratory
depression. Thus, there is a serious unmet need for alternatives to current treatment options for patients suffering
with chronic pain. One of the main drivers of chronic pain is inflammation following tissue injury or nerve injury
caused by increased levels of cytokines such as tumor necrosis factor α (TNF), and a positive correlation exists
between TNF levels and pain intensity. TNF can bind to its TNFR1 receptor located on the terminals of primary
afferent nociceptors to directly increase their activity, and can also stimulate pro-inflammatory cytokine
production and immune cell activation. Our preclinical work has identified TGFβ-activated kinase 1 (TAK1), a
key signaling element in the mediated TNF pro-survival/inflammatory response pathway. TAK1 plays a crucial
role in facilitating activation of protein kinase-mediated signaling pathways implicated in the pathogenesis of
chronic pain processes, and as a result has emerged as a novel target for regulating chronic pain and
inflammation linked to enhanced TNF signaling. Our recent discovery of the takinib scaffold has identified a
highly selective, potent (IC50 ~2.5nM), and orally bioavailable small molecule inhibitor of TAK1 (takinib analog
HS-276). Preclinical studies have demonstrated that TAK1 inhibition with parent takinib produces a 9-fold
reduction in TNF levels alongside reduced levels of other cytokines and chemokines involved in pro-inflammatory
responses. Also, TAK1 inhibition with parent takinib prevented mechanical and thermal heat pain, pain-related
depressive behavior, and edema in a model of inflammatory pain. Furthermore, parent takinib treatment in this
model reduced pro-inflammatory cytokine and chemokine protein expression. In order to successfully attain
proof-of-concept for takinib analog HS-276, this project includes three Specific Aims: Aim 1 – Evaluate the
pharmacokinetics of HS-276 regarding blood-brain barrier (BBB) bioavailability. Aim 2 – Determine the
established (therapeutic) analgesic potential of HS-276 in a monosodium urate-induced arthritis mouse model
of inflammatory pain evidenced by reduction in mechanical and thermal pain, as well as inflammatory cytokines.
Aim 3 – Deter...

## Key facts

- **NIH application ID:** 10151730
- **Project number:** 1R43NS119087-01A1
- **Recipient organization:** EYDIS BIO, INC.
- **Principal Investigator:** TIMOTHY A HAYSTEAD
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,955
- **Award type:** 1
- **Project period:** 2021-09-08 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151730

## Citation

> US National Institutes of Health, RePORTER application 10151730, Evaluating the Blood-Brain Barrier Bioavailability and in vivo Efficacy Potential of a Novel TAK1 Inhibitor Targeting Chronic Pain (1R43NS119087-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10151730. Licensed CC0.

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