# Novel Retinoic Acid Receptor Alpha-Selective Antagonists

> **NIH NIH P50** · UNIVERSITY OF MINNESOTA · 2020 · $213,023

## Abstract

PROJECT SUMMARY
Animals deprived of vitamin A in their diet (VAD) exhibit male sterility. All trans retinoic acid (ATRA), an active
metabolite of vitamin A, functions by binding to the nuclear retinoic acid receptors (RARs), of which there are
three isoforms α, β, and γ. We and others have shown the importance of ATRA signaling via the RARα receptor
in particular during spermatogenesis by gene targeting. Rara-/- mice are viable and healthy but the males are
sterile, with defects in spermatogenesis similar to that seen in mice maintained on a VAD diet. Following up on
observations of ‘testicular toxicity’ in rats treated with a pan-RAR antagonist, we have shown that indeed,
spermatogenesis is inhibited in male mice after treatment with this orally bioavailable compound, and importantly,
that the induced sterility is reversible. Our toxicology studies did not reveal any detectable side effects and normal
progeny were sired after restoration of fertility. This suggests that antagonizing RAR signaling and RARα in
particular, has potential as a novel and non-steroidal hormone-based approach to male contraception. The
objective in this application is to identify retinoids with that selectively antagonize RAR α and to evaluate their
therapeutic efficacy and reversibility. In Specific Aim 1, we propose to design, synthesize, and evaluate the in
vitro activity, binding, and ADMET properties of RARα-selective antagonists. Binding studies will utilize
isothermal titration calorimetry, differential scanning fluorimetry, surface plasmon resonance, microscale
thermophoresis, and X-ray crystallography; activity studies will use a luciferase reporter assay; and
pharmacological profiles will be assessed. Specific Aim 2 will then assess the in vivo effects of the most
promising RARα-selective antagonists on spermatogenesis. After the initial morphological analysis, we will
conduct fertility studies and develop dosing regimens for the most promising candidate molecules to determine
the lowest doses and longest dosing periods at which efficient induction of sterility with complete reversibility
could be achieved. Specific Aim 3 will then move to testing the lead candidate drug in a non-human primate, the
common marmoset, model in a small scale trial to set the stage for future pre-clinical trials. Finally, we have
observed in both our genetic and pharmacological models that one of the physiological processes in
spermatogenesis that is extremely sensitive to altered retinoid signaling is spermiation. In Specific Aim 4, we
therefore propose to determine both the quantitative global proteome and the quantitative phospho-proteome in
particular during spermiation using dissected segments of testicular tubules and analysis by mass spectrometry.

## Key facts

- **NIH application ID:** 9931061
- **Project number:** 5P50HD093540-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** DEBRA J. WOLGEMUTH
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $213,023
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931061

## Citation

> US National Institutes of Health, RePORTER application 9931061, Novel Retinoic Acid Receptor Alpha-Selective Antagonists (5P50HD093540-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931061. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*