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Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D

Award Number: R01CA258887
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D - Emerging evidence implies that protein acetyltransferases play a crucial role in diverse biological processes and various human diseases including cancer. Protein N-terminal acetyltransferase D (NatD), also known as Naa40, Nat4, or Patt1, is a unique member of protein N-terminal acetyltransferases because it only acetylates histones H2A and H4 that share the identical N-terminal sequence of SGRGK. NatD has been reported to play an important role in a variety of processes including remodeling of chromatin structure, cell migration and invasion, and apoptosis. The elevated level of NatD in human lung and colorectal cancer tissues correlates with poor clinical outcomes. Moreover, loss of NatD suppresses human lung cancer cell invasion and decreases the tumor growth in colorectal cancer xenograft mice models. Hence, we hypothesize that NatD is a compelling target for the development of novel cancer therapeutics for lung and colorectal cancers. However, there are no specific small molecule probes available for NatD to decipher the functions of NatD acetyltransferase activity in cancer. To fill this gap, our long-term goal is to discover novel, potent, and selective small molecule NatD inhibitors. For this application, we will employ a series of facile and reproducible high-throughput screening (HTS) assays with orthogonal readouts to screen 400,000 diverse compounds from selected chemical libraries at the Chemical Genomics Facility at Purdue Institute for Drug Discovery. Then we will characterize active compounds in structural, mechanistic, selectivity, and cell-based studies. Upon completion of this project, we expect to identify potent and selective first-in-class NatD small molecule inhibitors as chemical probes for NatD function in cells. The knowledge gained from this project would expedite the development of NatD modulators and our understanding of NatD-regulated pathways in cancer patients.


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 = $522,605 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	4	12/4/2024	NON-COMPETING CONTINUATION	$470,345
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	002	4	6/9/2025	NON-COMPETING CONTINUATION	$52,260
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $522,605

Issue Date FY: 2024 ( Subtotal = $496,475 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$26,132
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	3	11/16/2023	NON-COMPETING CONTINUATION	$470,343
														Subtotal = $496,475

Issue Date FY: 2023 ( Subtotal = $560,032 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	2	3/17/2023	NON-COMPETING CONTINUATION	$45,717
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	2	12/1/2022	NON-COMPETING CONTINUATION	$514,315
														Subtotal = $560,032

Issue Date FY: 2022 ( Subtotal = $559,725 )
2022	2022	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	1	11/29/2021	NEW	$559,725
														Subtotal = $559,725

Grand Total All Awards = $2,138,837

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Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D

Award Number: R01CA258887

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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