# Project 2: Development of Small Molecule Inhibitors of IL-17A Pathway for Treatment of Severe Asthma

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $784,421

## Abstract

ABSTRACT – PROJECT 2 
There are 2.5 million severe asthma patients in US. These patients are typically unresponsive, or poorly 
responsive to currently available asthma drugs. Therefore there is high unmet medical need for these patients. 
Several studies have suggested a central role for IL-17 (also called IL-17A) in severe asthma. Project 2's 
studies in the Program during Cycle I revealed the importance of IL-17 signaling pathways in the pathogenesis 
of asthma. The overall goal of Cycle II will focus on developing new therapeutic agents to block IL-17A 
pathway for the treatment of severe asthma. Project 2 was selected in 2015 to receive NCAI-CC support to 
begin to advance discoveries into novel therapies for severe asthma. Using IL-17R-deficient mice, Project 2 
demonstrated the critical role of IL-17A signaling in High-Fat Diet-induced airway hyperreactivity and 
Aspergillus-induced animal model of severe asthma. Thus, Project 2 hypothesizes that the IL-17A pathway is 
an important target for the treatment of severe and steroid-resistant asthma. Through computer-aided virtual 
screening based on the crystal structure of IL-17RA/IL-17A complex, Project 2 has identified one small 
molecule lead compound (A18) that inhibits IL-17A binding to IL-17RA in in vitro biochemical assay, in IL-17A- 
induced gene expression in cultured cells and in preclinical studies, i.e. attenuation of IL-17A-dependent 
neutrophilia, airway inflammation, and airway hyper-reactivity. Project 2 has also developed a decoy peptide of 
Act1 (adaptor for IL-17R) to inhibit IL-17A intracellular signaling, and IL17A biomarkers that will facilitate the 
identification of patient populations responsive to IL-17A inhibitors. Project 2 aims to (1) further optimize the 
A18 structure for better bioactivities with drug-like properties for a 2nd generation of lead compound(s) and 
develop peptidomimetics based on the decoy peptides; (2) validate A18, A18 derivatives and peptidomimetics 
in IL-17A-induced pulmonary neutrophilia, HFD- and Aspergillus-induced severe asthma models in 
collaboration with Aronica's lab and the Animal Core (Dr. Asosingh); (3) partnering with Novartis, Project 2 will 
collaborate with Project 1 on defining the Biomarkers for IL-17A-targeted treatment. Additionally, Project 2 will 
interact with the regulatory experts through Core B for pre-IND advice from the FDA in order to submit the 
required data for an IND application to move the small molecule development candidate into the clinic. As part 
of the commercialization plan, Project 2 is enthusiastic to explore the possibility of developing the platform of 
small molecule and peptidomimetic strategy through the creation of a start-up in Cleveland. Core B will work 
with Project 2 to identify team members for the start-up with prior life sciences technology start-up experience 
in order to, raise capital to invest in de-risking the technology to make it more attractive for joint development 
with a phar...

## Key facts

- **NIH application ID:** 9986007
- **Project number:** 5P01HL103453-10
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Serpil C. Erzurum
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $784,421
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986007

## Citation

> US National Institutes of Health, RePORTER application 9986007, Project 2: Development of Small Molecule Inhibitors of IL-17A Pathway for Treatment of Severe Asthma (5P01HL103453-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986007. Licensed CC0.

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