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Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

Award Number: R21CA273632
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs - Project Summary. While recent efforts have identified the need for methodologies capable of inactivating oncoproteins, current intervention strategies have left much of the proteome “undruggable.” In response the NCI has recognized this challenge as outlined in PAR-22-216 by incentivizing the development of new molecular targeting agents based on specific signaling pathways activated during the process of tumorigenesis or tumor progression. This program proposes an important next step in reaching these goals by providing a platform for the rapid development and characterization of heterobifunctional molecules capable of inducing degradation of cancer related metalloenzymes with new molecular targeting agents. In this program, our team will develop proteolysis targeting chimeras (PROTACs) containing state-of-the-art metal-binding pharmacophores (MBPs) with the ultimate goal of achieving isoform-selective degradation of jumonji C-domain containing lysine demethylases. Current strategies to inhibit conserved catalytic domain Jumonjis (JMJCs) involve targeting the α-ketoglutaric acid (2OG) substrate-accepting active site of JMJCs with inhibitors that can coordinate to the iron ion in the active site. Targeting the histone-binding helper domain of JMJCs generates additional isoform selectivity. However, no inhibitor has been shown to be selective for only one isoform of JMJCs. We have chosen to take a targeted degradation approach in order to increase the surface area of the peripheral interaction by recruiting an E3 ligase. This program will demonstrate how the potential protein- protein interaction induced by these chimeras can be leveraged to induce selective degradation of metalloproteins (`MetalloPROTACs') through rational MBP and linker design and will serve as a platform for the study of cancer biology, as well as laying the foundation for future development of therapeutic agents.


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: 2026 ( Subtotal = $0 )
2026	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $159,260 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	6/24/2024	NON-COMPETING CONTINUATION	$159,260
														Subtotal = $159,260

Issue Date FY: 2023 ( Subtotal = $205,385 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	1	6/14/2023	NEW	$205,385
														Subtotal = $205,385

Grand Total All Awards = $364,645

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Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

Award Number: R21CA273632

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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