# Development of Potent and non-toxic rexinoids to prevent non-melanoma skin cancer

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $610,112

## Abstract

Abstract:
Non-melanoma skin cancer (NMSC), which include basal cell carcinoma (BCC) and squamous cell carcinoma
(SCC) is one of the most common types of cancers in the US. Due to compromised immunity, solid organ
transplant recipients (SOTRs) are at a much higher risk for NMSC and it often becomes the cause of death in
SOTRs. Prevention of NMSC is an ideal strategy, particularly for immune compromised populations. Rexinoids
are small molecule drugs and are able to prevent skin cancer. However, some of the adverse effects may lead
to non-compliance in their use. We have developed two distinct classes of structures of rexinoids: UAB30 and
UAB20, which are highly selective, non-toxic and orally bioavailable RXR agonists. These agents are also highly
effective in preventing skin cancer as shown in our preliminary data. Both UAB30 and UAB20 do not cause
hyperlipidemia, an effect usually associated with clinically approved rexinoids. Dampening cancer associated
inflammatory biomarkers is also an attractive property of these agents. Thus, our enthusiasm for further
developing highly effective analogs of these agents as cancer chemopreventive agents has prompted us to
submit this proposal. Guided by x-ray crystallography and biophysical studies, we propose to develop novel
analogs of UAB30 & UAB20 with enhanced potency than parent compounds, with suitable pharmacokinetics for
chronic administration and without any overt toxicity. Low energy molecular conformation of UAB30 fit well into
the RXR ligand-binding pocket (LBP). Our strategy is to improve the potency significantly without distorting the
molecular conformations of these two agents. Therefore, we propose to substitute a hydrogen atom with a
halogen and/or a heteroatom. Because of the electronegativity of fluorine and the strength of carbon-fluorine
bond, we have reasoned that strategic introduction of fluorine will improve the potency, oral bioavailability,
metabolic stability and pharmacokinetics of the newly synthesized analogs. Heteroatoms such as nitrogen can
modulate the polarity (logP) value significantly. Therefore, we have proposed to substitute a single carbon of
tetralone ring of the UAB30 with a nitrogen. Individually and collectively, these modifications will significantly
contribute to the potency of UAB30 analogs and will make them ideal agents for pre-clinical evaluation. Similarly,
for UAB20, x-ray crystal structures reveal that a five membered heterocyclic ring is accommodated more
favorably and make interactions within the LBP. Therefore, we have proposed to substitute the phenyl ring with
heterocyclic rings. These modifications will also modulate the logP and improve pharmacokinetics of these new
analogs. Our co-investigator in this application has developed unique murine models of the NMSC, which
recapitulate human pathobiology of the disease both in normal population and in SOTRs. These models will be
employed in the proposed investigations to define the most effective and no...

## Key facts

- **NIH application ID:** 10562891
- **Project number:** 1R01CA276683-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Venkatram Reddy Atigadda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $610,112
- **Award type:** 1
- **Project period:** 2023-03-07 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10562891

## Citation

> US National Institutes of Health, RePORTER application 10562891, Development of Potent and non-toxic rexinoids to prevent non-melanoma skin cancer (1R01CA276683-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10562891. Licensed CC0.

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