# Identification of REV-ERB inverse agonists for cancer immunotherapy

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $614,469

## Abstract

PROJECT SUMMARY
 While immunotherapy is a breakthrough in our fight against cancer, only a subset of patients display robust
and long-lasting responses highlighting the critical need for novel approaches to be used alone or in combination
with current therapeutic regimens. TH17 cells, which express the lineage defining transcription factor RORgt,
have emerged as targets to enhance antitumor immunity, with RORg agonists currently in Phase 1/2 clinical
trials. The transcriptional repressors REV-ERBa and REV-ERBb are often co-expressed in the same tissues
as RORg(t) and bind the same DNA response elements, which suggests mutual cross talk and co-regulation of
their target genes. Our preliminary data demonstrates that the REV-ERBs are ligand-regulated transcription
factors and play critical roles in TH17 responses, including regulation of IL-17A expression through competition
with RORgt at their shared DNA consensus sequence(s), and regulation of RORgt expression itself. We have
generated small molecule ligands that enhance the REV-ERBs repressive function and inhibit TH17 cell
development in vitro and in vivo. Thus, we hypothesize that identification of ligands that inhibit the REV-ERBs
repressive activity will enhance TH17 responses and antitumor immunity. In order to identify ligands that inhibit
REV-ERB activity, we have designed a high-throughput screening (HTS) compatible primary assay that detects
direct ligand binding to each receptor. Our goal is to implement a full HTS-campaign using the Scripps
Institutional Drug Discovery Library (SDDL) to identify, validate, and characterize potent small molecule inverse
agonists of REV-ERB activity. To achieve our goal, we will miniaturize our assay into a 1,536-well plate format
and upon meeting HTS automation criteria, carry out a “full-deck” HTS campaign to screen the >640,000
compounds in the SDDL (Aim 1). Cheminformatic analysis of “hits” will help identify the most promising leads
by structural clustering, bioinformatics analysis of compounds to determine promiscuity, and scaffold analysis to
determine ease of chemical synthesis and tractability for further medicinal chemistry efforts to perform structure-
activity relationship studies. In Aim 2, we will use a cascade of follow up assays to validate screening hits,
determine specificity, and begin to understand mechanism of action of REV-ERB-mediated transcriptional
activity. Finally, in Aim 3, validated HTS hits will be advanced to early medicinal chemistry for lead optimization
and characterization of novel negative regulators of REV-ERBa/b. We expect that completion of this application
will deliver multiple structurally distinct REV-ERB inverse agonists that exhibit suitable levels of cellular activity,
potency, and selectivity. Our collaborative research team has a strong track record of performing high-throughput
screens, selective optimization of scaffolds, and in vitro and in vivo characterization of compounds. Collectively,
our screening a...

## Key facts

- **NIH application ID:** 10401264
- **Project number:** 5R01CA241816-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Laura A Solt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $614,469
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401264

## Citation

> US National Institutes of Health, RePORTER application 10401264, Identification of REV-ERB inverse agonists for cancer immunotherapy (5R01CA241816-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401264. Licensed CC0.

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