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Identification of small molecule inhibitors of the DDI2 protease

Award Number: R01CA279255
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Identification of small molecule inhibitors of the DDI2 protease - PROJECT SUMMARY Proteasome inhibitors are currently being used in the clinic against Multiple myeloma. This approach is thought to work at least in part because cancer cells appear to rely more heavily on proteasomes than do normal cells. However, our previous studies showed that proteasome inhibition invokes an adaptive program driven by the transcription factor NRF1 which upregulates proteasome genes resulting in the recovery of proteasome activity, thus limiting the efficacy of this approach. Consistent with this notion, our preliminary data suggest that depletion of NRF1 potentiates the action of proteasome inhibition therapy in a breast cancer xenograft model. Taking advantage of the fact that a protease DDI2 is essential for NRF1 activation, here we propose to identify small molecule inhibitors of this protease that could be used to enhance the efficacy of proteasome inhibitors. Moreover, based on our preliminary data that showed depleting DDI2 in itself retards tumor growth, DDI2 inhibitors could also find use as a single-agent. Based on our pilot screen that demonstrates feasibility and consistent with the goals of PAR-20-271, this 4-year project will pursue the following specific aims. In AIM 1, we will express and purify DDI2 protein and perform high-throughput screens using a protein thermal shift (PTS) assay to identify compounds that bind DDI2. In AIM 2, we will perform hit selection, confirmation and profiling using a panel of secondary assays that includes orthogonal and counter-screen assays as well as biophysical assays. In AIM 3, we will perform hit validation, hit expansion, probe selection and profile the mechanism of action of hits, followed by cellular assays to assess DDI2 target engagement, impact on the DDI2-NRF1 axis and cancer cell apoptosis.


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: 2025 ( Subtotal = $777,229 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	3	5/2/2025	NON-COMPETING CONTINUATION	$0
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	003	3	7/24/2025	SUPPLEMENT FOR EXPANSION	$77,925
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	002	3	5/28/2025	NON-COMPETING CONTINUATION	$69,931
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	3	3/13/2025	NON-COMPETING CONTINUATION	$629,373
														Subtotal = $777,229

Issue Date FY: 2024 ( Subtotal = $749,568 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	2	3/15/2024	NON-COMPETING CONTINUATION	$636,295
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	002	2	4/17/2024	NON-COMPETING CONTINUATION	$35,348
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	2	4/10/2024	SUPPLEMENT FOR EXPANSION	$77,925
														Subtotal = $749,568

Issue Date FY: 2023 ( Subtotal = $730,979 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	1	4/10/2023	NEW	$730,979
														Subtotal = $730,979

Grand Total All Awards = $2,257,776

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Identification of small molecule inhibitors of the DDI2 protease

Award Number: R01CA279255

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/10/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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