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Targeting crotonyl-lysine chromatin readers to disrupt pathogenic gene expression in leukemia

Award Number: DP5OD026380
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Targeting crotonyl-lysine chromatin readers to disrupt pathogenic gene expression in leukemia - PROJECT SUMMARY/ABSTRACT To support the cellular demands of unchecked proliferation and to maintain a malignant cell state through successive rounds of cellular division, cancer cells depend on lineage-specific, dysregulated gene expression programs. Thus, the chromatin regulators that underlie chromatin-dependent transcription control have been considered attractive targets to disrupt or diminish pathogenic transcriptional signaling. Previously, I led a research effort that established ENL, a transcriptional co-activator and chromatin reader protein, as a critical requirement for the survival of acute leukemia in cellular and animal model systems. Notably, its YEATS domain, a crotonyl-lysine-binding chromatin reader domain that anchors ENL at the promoters of transcriptionally active genes, is required for the pro-proliferative effects of ENL in leukemia. Moreover, preliminary data suggests that KAT6A, a histone acetyltransferase and crotonyl-lysine chromatin reader protein, is also required for acute leukemia pathogenesis. Here, I propose to further consider crotonyl-lysine reader proteins as potential therapeutic opportunities in acute leukemia with the following three specific aims. In the first aim, I will determine the cellular pathways and co-factors regulating response and resistance to loss of ENL in acute leukemia. Genetic experiments proposed within this aim will determine the cellular pathways and co-factors regulating ENL target biology to understand its mechanism of action in promoting leukemia cell proliferation and survival. In the second aim, I will test the hypothesis that the ENL YEATS domain can be disrupted by small-molecule inhibitors, which will serve both as chemical probes of ENL protein function and as starting points for translational development of ENL-targeted leukemia therapy. I will apply high-throughput chemical screens, structure-based drug design, and iterative medicinal chemistry to discover and optimize first-in-class ENL YEATS inhibitors. In the third aim, I will assess the role of crotonyl-lysine recognition by KAT6A in leukemia pathogenesis; I will use genetic approaches and targeted protein degradation to determine whether crotonyl-lysine recognition by the double PHD finger domain (DPF) of KAT6A is required for acute leukemia survival. Each proposed aim operates within early-stage drug discovery efforts (i.e. target validation and chemical tool discovery) and if successful, will provide biological insights and chemical tools that will enable timely translational development of novel, molecularly-targeted cancer medicines. In keeping with the model of open-innovation in academic drug discovery, all chemical probes, biological tools, and genomic datasets derived from this work will be made publicly and freely available, without restriction on use, so to broaden and accelerate the impact of this work.


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 = $0 )
2024	2022	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	5	4/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $483,750 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	001	5	8/30/2022	NON-COMPETING CONTINUATION	$483,750
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	4	5/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $483,750

Issue Date FY: 2021 ( Subtotal = $483,750 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	4	9/8/2021	NON-COMPETING CONTINUATION	$483,750
														Subtotal = $483,750

Issue Date FY: 2020 ( Subtotal = $483,750 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	3	8/25/2020	NON-COMPETING CONTINUATION	$483,750
														Subtotal = $483,750

Issue Date FY: 2019 ( Subtotal = $483,750 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	2	8/12/2019	NON-COMPETING CONTINUATION	$483,750
														Subtotal = $483,750

Issue Date FY: 2018 ( Subtotal = $483,750 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	1	9/7/2018	NEW	$483,750
														Subtotal = $483,750

Grand Total All Awards = $2,418,750

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Targeting crotonyl-lysine chromatin readers to disrupt pathogenic gene expression in leukemia

Award Number: DP5OD026380

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/07/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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