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Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands

Award Number: R01CA194496
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands - PROJECT SUMMARY Hormonal therapies have been revolutionary in the treatment of women with estrogen receptor positive (ER+) breast cancers, greatly enhancing survival. ER-targeted hormonal therapies include selective estrogen receptor modulators SERMs, such as tamoxifen, and selective estrogen receptor downregulators (SERDs), such as fulvestrant, whereas aromatase inhibitors block the biosynthesis of estrogen. These therapies have significant side effects, and their prolonged use can lead to chemoresistance in about one- third of treated women, often resulting in more aggressive cancers. Furthermore, tamoxifen use is associated with increased incidence of endometrial thickening and hyperplasia, polyps and cancer. Recent studies have identified novel pathways involving the 7-transmembrane spanning G protein-coupled receptor GPER in patients undergoing SERM/SERD therapies. Cross-reactive pharmacological agonism of GPER contributes to both hormonal resistance and off-target effects in the uterus as all clinically approved anti- estrogens act as agonists for GPER and stimulate these pathways. This critical issue of ER/GPER selectivity has not been addressed in the development of SERM and SERD drugs. In our previous work, we discovered and characterized novel selective ligands for GPER that do not bind ERα or ERβ.Recently, we discovered a novel small molecule that for the very first-time targets ER without interference of GPER. As current anti-estrogens do not discriminate between ERα/β and GPER, our newly identified small molecule affords the opportunity to create novel ligands and therapeutic agents to selectively target ERα. Through chemical modifications to this first-generation ERα-selective compound, we have improved the affinity, receptor-selectivity and antagonist/agonist profile with the ultimate goal of creating truly ERα- selective antagonists. The specific aims of this proposal are to: 1. Synthesize and resolve the bioactive enantiomer of optimized ERα-targeted AB-SERD compounds with GPER anti-selectivity; 2. Prioritize compounds through in vitro methods including receptor binding, cell signaling, proliferation and toxicity and 3. Determine in vivo anti-tumor and ADMET properties of lead compounds, employing ER-dependent and anti-hormone-resistant transgenic, xenograft and PDX tumors. The successful completion of these studies will identify innovative enantiospecific compounds as unique pharmacological tools for delineating the individual functions of ER and GPER, and also initiating the development of first-in-class therapeutic agents, with the goal of reducing anti-hormone resistant recurrence of breast cancer, enhancing survival and the quality of life for the greater than 200,000 women annually diagnosed with ER-positive breast cancer.


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 = $486,792 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	8	8/1/2024	NON-COMPETING CONTINUATION	$486,792
														Subtotal = $486,792

Issue Date FY: 2023 ( Subtotal = $502,165 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	001	7	8/17/2023	NON-COMPETING CONTINUATION	$502,165
2023	2020	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	5	6/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $502,165

Issue Date FY: 2022 ( Subtotal = $525,537 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	000	6	8/23/2022	COMPETING CONTINUATION	$336,705
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Cancer Treatment Research	001	6	8/26/2022	COMPETING CONTINUATION	$188,832
														Subtotal = $525,537

Issue Date FY: 2020 ( Subtotal = $320,000 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	5	8/18/2020	NON-COMPETING CONTINUATION	$320,000
														Subtotal = $320,000

Issue Date FY: 2019 ( Subtotal = $310,400 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	001	4	8/20/2019	NON-COMPETING CONTINUATION	$66,305
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	4	8/15/2019	NON-COMPETING CONTINUATION	$244,095
														Subtotal = $310,400

Issue Date FY: 2018 ( Subtotal = $320,000 )
2018	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	3	8/2/2018	NON-COMPETING CONTINUATION	$320,000
														Subtotal = $320,000

Issue Date FY: 2017 ( Subtotal = $320,000 )
2017	2017	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	2	8/23/2017	NON-COMPETING CONTINUATION	$320,000
														Subtotal = $320,000

Issue Date FY: 2016 ( Subtotal = $320,000 )
2016	2016	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	1	9/7/2016	NEW	$320,000
														Subtotal = $320,000

Grand Total All Awards = $3,104,894

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Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands

Award Number: R01CA194496

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/07/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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