# Small molecule inhibitor of CD40 signaling for the control of inflammatory bowel disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $329,725

## Abstract

PROJECT SUMMARY
 Despite advances in the treatment of inflammatory bowel disease (IBD), many patients fail to respond to
therapy. Thus, there is a need to find new therapeutic approaches against IBD. The CD40-CD154 pathway is a
known target against IBD and other inflammatory disorders. Clinical trials indicated that CD40 blockade with
anti-CD154 antibodies reduced inflammation. However, the anti-CD154 antibodies caused thrombosis
(unrelated to inhibition of CD40). Moreover, other approaches to cause global inhibition of CD40 are predicted
to increase the risk of opportunistic infections. Identification of a strategy to inhibit CD40-induced inflammation
that does not induce thrombosis or opportunistic infections can be a major advance in the treatment of IBD.
 We uncovered that blocking the interaction between CD40 and an intracellular adaptor protein inhibits pro-
inflammatory responses induced by CD40 while leaving protection against an opportunistic pathogen intact.
We identified a small molecule that binds the adaptor protein, blocks CD40 signaling, reduces pro-
inflammatory responses in vitro and diminishes intestinal inflammation in mouse models of IBD. The compound
did not impair resistance against an opportunistic pathogen.
 The compound has suboptimal solubility and microsomal stability. While some analogs designed to date
showed some improvement in solubility or microsomal stability, further optimization is necessary. The objective
of this application is to develop an optimized inhibitor that will be tested in mouse and human IBD systems.
The central hypothesis is that a potent analog with improved solubility and microsomal stability will optimally
block CD40 signaling, and markedly suppress inflammation in mouse models of IBD as well as CD40-driven
inflammatory responses in intestinal cells from patients with IBD. To test this hypothesis, we will design and
generate analogs of the compound, test their properties, perform signaling studies in reporter cells and
intestinal cells and test the lead inhibitor in animal models of IBD. In the first specific aim we will use structure
activity relationships with the aid of a docking model to design and generate analogs of the compound in order
to improve solubility and microsomal stability. We will examine their ability to inhibit CD40 signaling and their
affinity for the adaptor protein. In the second aim, we will test the most potent analogs to determine if they
inhibit CD40 signaling in vivo. In the third aim, we will determine if the lead analog reduces intestinal
inflammation in mouse models of IBD and inhibits CD40-induced expression of inflammatory molecules in
intestinal cells from IBD patients. The proposed work may lead to a new strategy to treat IBD based on a novel
approach to inhibit CD40 signaling.

## Key facts

- **NIH application ID:** 10848395
- **Project number:** 5R01DK133903-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** CARLOS S SUBAUSTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $329,725
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848395

## Citation

> US National Institutes of Health, RePORTER application 10848395, Small molecule inhibitor of CD40 signaling for the control of inflammatory bowel disease (5R01DK133903-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10848395. Licensed CC0.

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