# Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $672,000

## Abstract

Abstract
The complications of diabetes, particularly impaired wound healing and diabetes-associated nephropathy, are
major causes of morbidity and mortality in patients with types 1 and 2 diabetes. The RAGE extracellular domains
are heterogeneous and RAGE ligands may bind at spatially-distinct sites on these domains, thereby indicating
that the use of small molecules or antibodies targeted to the extracellular domains, may be ineffective. We have
discovered that the interaction of the cytoplasmic tail of RAGE (ctRAGE) with the intracellular formin molecule,
DIAPH1, is essential for RAGE-mediated signal transduction. We previously performed a high-throughput screen
of >59,000 compounds with the goal to block the interaction of ctRAGE with DIAPH1. We identified two lead
series (LS) that fulfill key criteria for drug-like properties; from one of the series, LSII, RAGE229 emerged as a
plausible lead for clinical development because of efficacy, favorable pharmacokinetic profile and promising
early-stage off-target and toxicity testing. In vivo efficacy was also demonstrated, as administration of RAGE229
attenuated inflammation in a delayed type hypersensitivity experiment in mice, reduced myocardial infarct size
upon ligation and reperfusion of the left anterior descending coronary artery in diabetic mice, and reduced
multiple parameters of diabetes-associated kidney pathology and impaired wound healing in diabetic mice, all
versus vehicle, in both male and female mice. However, in late-stage testing, RAGE229 tested positive in the
Mini-AMES test. To address this liability, we have already prepared new analogs of RAGE229; these analogs
retain potency but are negative in the Mini-AMES test. In addition, we have made significant progress in
developing back-up candidates in the LS I. Importantly, a lead benchmark compound within LSI tested negative
in the Mini-AMES test as well. Our established, multi-disciplinary team is now well-poised to move forward
aggressively at this critical juncture to identify lead candidate molecules for LSII and the back-up LSI for ultimate
clinical development for diabetic complications. Our drug discovery goals, supported by extensive preliminary
data are: 1) to identify potent, selective, and safe candidate analogs of LSII; and 2) to develop LSI backup
candidates with a different scaffold to mitigate risk to our RAGE program. If successful, our work will set the
stage for the development and clinical testing of a novel class of disease-modifying agents for diabetic
complications.

## Key facts

- **NIH application ID:** 10055037
- **Project number:** 1R01DK122456-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ravichandran Ramasamy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $672,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055037

## Citation

> US National Institutes of Health, RePORTER application 10055037, Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications (1R01DK122456-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10055037. Licensed CC0.

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