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Discovery of small molecules targeting the histone acetylation reader ENL

Award Number: R01CA255506
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2020
PERIOD OF PERFORMANCE END DATE: 12/01/2025

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Discovery of small molecules targeting the histone acetylation reader ENL - PROJECT SUMMARY The mixed-lineage leukemia (MLL) gene rearrangements account for approximately 80% of infant acute lymphoblastic leukemia (ALL) and 35-50% of infant acute myeloid leukemia (AML). Patients bearing rearrangements of the MLL gene are associated with dismal prognosis and particularly poor response to standard treatments. Up-to-date, effective therapies for this subtype of fatal disease are still lacking. Molecularly, inter-chromosomal translocations of MLL lead to in frame fusions of the N-terminus of MLL to the C-terminus of various fusion partners, which are known as the “driver” lesions of the diseases. Among more than 70 MLL fusion partners, a small subset of fusions account for most leukemogenic cases. In ALL, over 90% MLL rearrangements involve only four fusion partners: AFF1, AF9, ENL, and AF10, all are components of the super elongation complex (SEC) or the complex of the histone H3K79 methyltransferase DOT1L. It is believed that these MLL fusions share a common pathway by “hijacking” SEC or the DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading to the pathogenesis of leukemias. Studies from the applicant and others have demonstrated that ENL, a stoichiometric component of SEC and the DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally conserved YEATS domain. The applicant found that the YEATS domain of ENL functions as a reader of histone acetylation (Cell, 2014, 159:558-71). Importantly, the acetylation reading function of the YEATS domain is essential for growth and survival of the MLL-rearranged leukemic cells (Nature, 2017, 543:265-269). These key findings provide the proof of concept that targeting the YEATS domain of ENL is a potentially valuable therapeutic option in treatment of MLL-rearranged leukemias. The goal of this proposal within the scope of this FOA is to develop potent and selective inhibitors of the ENL YEATS domain. The specific aims of the proposal are to (1) conduct a high-throughput screening for ENL small-molecule inhibitors; (2) validate and evaluate candidate hits by orthogonal assays; and (3) characterize hits in cell-based assays. The inhibitors obtained from the proposed study will serve as tool compounds to study the functions and mechanisms of ENL in promoting MLL-fusion proteins in gene regulation and disease maintenance. These compounds will also provide the basis for further development of small molecules for targeted therapies of MLL-translocated leukemias. Preclinical studies suggest that BET inhibitors exhibit limited efficacy as single agents. Selective and potent ENL inhibitors provided by this project will be an important tool to test the synergistic effect of ENL and BET inhibitions, providing an innovative therapeutic strategy for the treatment of MLL-rearranged leukemias.


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	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	000	4	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $408,872 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	000	4	11/13/2023	NON-COMPETING CONTINUATION	$387,352
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$21,520
														Subtotal = $408,872

Issue Date FY: 2023 ( Subtotal = $431,498 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	002	3	3/16/2023	NON-COMPETING CONTINUATION	$35,225
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	000	3	12/1/2022	NON-COMPETING CONTINUATION	$396,273
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	001	2	12/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $431,498

Issue Date FY: 2022 ( Subtotal = $439,725 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	001	2	5/10/2022	NON-COMPETING CONTINUATION	$35,895
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	000	2	11/18/2021	NON-COMPETING CONTINUATION	$403,830
														Subtotal = $439,725

Issue Date FY: 2021 ( Subtotal = $454,068 )
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Treatment Research	000	1	12/3/2020	NEW	$454,068
														Subtotal = $454,068

Grand Total All Awards = $1,734,163

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Discovery of small molecules targeting the histone acetylation reader ENL

Award Number: R01CA255506

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2020

PERIOD OF PERFORMANCE END DATE: 12/01/2025

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