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Identification of REV-ERB inverse agonists for cancer immunotherapy

Award Number: R01CA241816
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Identification of REV-ERB inverse agonists for cancer immunotherapy - 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 approach puts us in a unique position to identify, validate, and characterize novel REV-ERB- selective small molecule inverse agonists for the study of the REV-ERB’s function in enhancing TH17 responses and to determine whether targeting these receptors is a viable option for immunotherapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$2 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	000	5	8/19/2024	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Treatment Research	000	3	10/17/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $614,469 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	002	5	7/25/2022	NON-COMPETING CONTINUATION	$614,469
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Treatment Research	000	3	7/7/2022	NON-COMPETING CONTINUATION	-$289,604
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	001	4	7/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$289,604
														Subtotal = $614,469

Issue Date FY: 2021 ( Subtotal = $682,154 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Treatment Research	000	3	5/4/2021	NON-COMPETING CONTINUATION	$682,154
														Subtotal = $682,154

Issue Date FY: 2020 ( Subtotal = $643,014 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Treatment Research	000	2	4/21/2020	NON-COMPETING CONTINUATION	$643,014
														Subtotal = $643,014

Issue Date FY: 2019 ( Subtotal = $547,678 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Treatment Research	000	1	4/30/2019	NEW	$547,678
														Subtotal = $547,678

Grand Total All Awards = $2,487,313

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Identification of REV-ERB inverse agonists for cancer immunotherapy

Award Number: R01CA241816

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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