# Project 2: Design and Development of Third Generation RXR Rexinoids as Potential Chemoprevention Agents

> **NIH NIH P01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $131,141

## Abstract

Organ transplant patients who are immune-suppressed are at high risk to develop non-melanoma 
skin cancers (NMSC). Prevention of NMSC in this high risk population requires the development 
of effective drugs with minimal toxicity since these drugs are administered chronically. An FDA- 
approved drug has yet to be identified for use to prevent NMSC. We have developed a novel 
tissue-selective rexinoid, named UAB30, which acts as an agonist in epithelial tissues but not in 
liver. UAB30 is highly effective in multiple cancer prevention models while exhibiting minimal 
toxicity (especially lipid toxicity). UAB30 is currently evaluated in phase 1 human trials. 
Preliminary results (Core 3) show that UAB30 is highly effective in preventing the formation of 
papilloma, basal cell carcinoma, and squamous cell carcinoma in UVB-irradiated hairless mice. 
We have also shown that UAB30 up-regulates genes important for enhancing all-trans-retinoic 
acid biosynthesis in normal epithelium and in cancers. Thus, we hypothesize in this proposal that 
UAB30 (or other UAB30-like agonists) prevent NMSC by enhancing signaling through RXR-RAR 
heterodimers. In Aim 1, we propose studies to understand how rexinoids bind RXR and remodel 
the surface of the nuclear receptor to recruit coactivators. The importance of residues within the 
two putative molecular networks that bridge the rexinoid binding site to the coactivator binding 
site will be investigated using x-ray crystallography, Hydrogen-Deuterium Exchange Mass 
Spectrometry (HDX MS), and isothermal titration calorimetry (ITC). In Aim 2, we propose studies 
to understand if the molecular signatures of potency versus those of toxicity be revealed so that 
new 3rd -generation agonists are designed without toxicity. Structural studies on a series of 
methyl-derivatives of UAB30 have revealed a putative `hot-spot' in the ligand binding pocket that 
stimulates lipid biosynthesis and toxicity. We will examine the importance of this `hot-spot' by 
evaluating structures and dynamics of a series of potent rexinoids with known lipid profiles (potent 
rexinoids that induce lipid synthesis versus those that do not). A team of structural biologists with 
expertise in x-ray crystallography, mass spectrometry, thermodynamics, and biophysics has been 
assembled to address these aims. Project 2 provides information on the structure and dynamics 
of RXR, which we hypothesized, can be important for determining which rexinoids are potent and 
nontoxic. Project 2 will interact with Core 2 in designing new 3rd generation rexinoids, which will 
be evaluated in in vitro studies in Project 3 and in in vivo models in Core 3. The Program 
Integration section contains a complete developmental schema for 3rd generation rexinoids.

## Key facts

- **NIH application ID:** 10263922
- **Project number:** 5P01CA210946-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Matthew B Renfrow
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $131,141
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263922

## Citation

> US National Institutes of Health, RePORTER application 10263922, Project 2: Design and Development of Third Generation RXR Rexinoids as Potential Chemoprevention Agents (5P01CA210946-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10263922. Licensed CC0.

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