# Targeting IRAK1/4 in Myelodysplastic Syndromes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $481,139

## Abstract

Research in my laboratory has made critical findings related to the molecular, cellular,
and genetic basis of Myelodysplastic Syndromes (MDS), a complex and poorly understood
hematopoietic stem cell (HSC) failure syndrome. The complexity and heterogeneity of MDS, and
the lack of mouse models, remain as major obstacles to understanding and effectively treating
this disease. Overexpression of immune-related genes is widely reported in MDS, and chronic
innate immune pathway activation, primarily via Toll-like receptors (TLRs), increases the risk of
developing MDS. Multiple independent mechanisms contribute to hyperactivation of TLR
signaling in MDS, which converge on the central complex involving IRAK1, IRAK4, and TRAF6.
Based on our published and preliminary data, IRAK1 and IRAK4 (IRAK1/4), a dual kinase
complex is activated in MDS patients. Moreover, the importance of the IRAK1/4-TRAF6 complex
in primary MDS comes from our recent observation that describes genetic and pharmacologic
approaches to inhibit IRAK1/4 as effective agents to suppress TRAF6 and the MDS clone.
Collectively, these molecular and genetic alterations clearly implicate IRAK1/4-TRAF6 signaling
as a pathogenic driver and druggable complex in MDS. Therefore, we hypothesize that small
molecule dual inhibitors of IRAK1 and IRAK4 will suppress MDS-propagating cells. We derived
a novel chemical series of potent dual IRAK1/4 inhibitors. The lead compound shows potent
inhibition of IRAK1 and IRAK4 in MDS, efficacy at suppressing MDS cell viability and function in
vitro, and promising pharmacokinetic and pharmacodynamics properties in vivo. As such, the
objective of this proposal is to optimize and evaluate our candidate dual IRAK1/4 inhibitors in
human MDS cells in vitro (Aim 1), and in mouse and human MDS models in vivo (Aim 2). The
specific aims will provide necessary preclinical information on the therapeutic potential of
rationally designed dual IRAK1/4 inhibitors for future human MDS trials.

## Key facts

- **NIH application ID:** 9931213
- **Project number:** 5R01DK113639-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Daniel Starczynowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,139
- **Award type:** 5
- **Project period:** 2017-08-07 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931213

## Citation

> US National Institutes of Health, RePORTER application 9931213, Targeting IRAK1/4 in Myelodysplastic Syndromes (5R01DK113639-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9931213. Licensed CC0.

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