# Development of ITCH-activating IRAK4 degraders as dual-targeting drug candidates for the treatment of rheumatoid arthritis

> **NIH NIH R43** · PROGENRA, INC. · 2022 · $254,561

## Abstract

The interleukin-1 receptor-activated kinase 4 (IRAK4) is a serine/threonine kinase mediating the innate immune
and inflammatory response; it is expressed in numerous cell types. IRAKs are key regulators of inflammatory
signaling elicited by Toll-like receptors (TLRs), interleukin-1 receptor (IL-1R) and interleukin-18 receptor (IL18R).
Upon binding to the TLR, IRAK4 dimerizes and binds MyD88 adaptor protein to form a complex that facilitates
IRAK autophosphorylation and activation. In turn, the NFkB and MAPK pathways are activated. Activated NFkB
transcription factor regulates several proinflammatory cytokines, including IL-6 and IL-10. IRAK4 is critical to
murine and human anti-inflammatory responses, as shown in experiments with knockout/knockin mice. IRAK4
knockout mice are resistant to septic shock, and their cytokine production is impaired, while IRAK4 kinase-dead
knock-in mice are impaired in their ability to produce cytokines upon TLR agonist challenge. Thus, inhibition of
IRAK4 is seen as a therapeutic avenue for treating conditions characterized by overactivation of innate immunity
or inflammatory pathways, e.g., rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Several IRAK4
inhibitors have shown anti-inflammatory effects in preclinical models, and a few are in clinical trial for treatment
of RA, SLE, and psoriasis. Targeted protein degradation using heterobifunctional molecules called PROTACs,
which are composed of a target protein binder tethered to a ubiquitin E3 ligase binder, is a promising new
therapeutic modality. PROTACs remove all the target protein in the cell by E3- directed degradation, and thus
are more efficacious than simple pharmacological inhibitors, which can leave some target molecules intact or
become susceptible to resistance. They have impressive preclinical profiles, and several are in clinical trial for
cancer. Simple IRAK4 inhibitors have been reported, with three reaching clinical trials. A PROTAC that degrades
IRAK4 employing the E3 ligase cereblon is in Phase I clinical trial for dermatitis and hidradenitis suppurativa. In
the proposed project, Progenra will develop a novel IRAK-4 PROTAC using a different E3 ligase, ITCH; it will
have improved pharmacology and therapeutic efficacy with broader applications, compared with the cereblon
PROTAC and should be superior to the pharmacological inhibitors. ITCH-IRAK molecules designed to degrade
IRAK4 efficiently will be synthesized and characterized biochemically and biophysically in vitro, and cellular proof
of concept will be demonstrated using relevant cell models of inflammation. Chemical optimization and other
aspects of preclinical development will be conducted in Phase II.

## Key facts

- **NIH application ID:** 10545911
- **Project number:** 1R43AR081153-01A1
- **Recipient organization:** PROGENRA, INC.
- **Principal Investigator:** Kumar Suresh
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,561
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10545911

## Citation

> US National Institutes of Health, RePORTER application 10545911, Development of ITCH-activating IRAK4 degraders as dual-targeting drug candidates for the treatment of rheumatoid arthritis (1R43AR081153-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10545911. Licensed CC0.

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