Wednesday, September 17, 2025 9/17/2025

Targeting PRC1 in leukemia

Award Number: R01CA282082
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Targeting PRC1 in leukemia - Abstract Acute leukemia is an aggressive disease resulting from various genetic abnormalities and is characterized by the presence of undifferentiated blood cells. Emerging evidence shows that recurrence of acute leukemia results from the activity of leukemic stem cells (LSCs), which are resistant to chemotherapy, supporting the need for new pharmacological agents inducing differentiation of LSCs. The self-renewal and differentiation capacity of stem cells, including LSCs, are dependent on the activity of the Polycomb repressive complex 1 (PRC1). The core of all PRC1 complexes comprises heterodimeric complexes involving RING1B or RING1A and one of the PCGF1-6 paralogs, which catalyze monubiquitination of histone H2A (H2Aub) constituting a strong repressive mark. Simultaneous depletion of core PRC1 components RING1A/B results in a loss of H2Aub deposition, cell growth arrest and differentiation of acute leukemia cells driven by the oncogenes associated with expression of HOXA9. Therefore, blocking PRC1 activity with small molecules could lead to eradication of LSCs and differentiation of leukemic blasts. The major goal of this project is to develop potent small molecule inhibitors blocking the activity of PRC1 by a direct inhibition of the RING1B-BMI1 E3 ubiquitin ligase to induce differentiation of leukemic cells. To this end, we employed fragment-based screening followed by extensive medicinal chemistry to develop the first-in-class small molecules that directly bind to the RING1A/B proteins and inhibit PRC1 activity through blocking the interaction of the PRC1 complex with nucleosomes. Our first-generation inhibitor RB-3 decreases global level of H2Aub and induces differentiation in leukemia cells and primary AML samples. The goal of this proposal is to optimize this class of compounds and develop potent PRC1 inhibitors with optimized drug-like properties and pronounced in vivo efficacy in animal models of acute leukemia. We will employ extensive medicinal chemistry and structure-based design approach to optimize PRC1 inhibitors. All inhibitors will be characterized to determine binding affinity, inhibitory activity, and cellular activity to inhibit H2Aub. Best compounds will be extensively evaluated in a panel of leukemia cell lines. We will assess the mechanism of action of the PRC1 inhibitors and test their activity in the models of LSCs and in the primary AML patient samples. The optimized compounds will be assessed in vivo for their potential to block development of leukemia in mouse models of AML. Our studies will explore a new approach to induce differentiation of leukemia cells and LSCs and may lead to the development of highly valuable chemical probe compounds or novel pharmacologic agents for acute leukemia 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 = $624,980 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	3	8/26/2025	NON-COMPETING CONTINUATION	$624,980
														Subtotal = $624,980

Issue Date FY: 2024 ( Subtotal = $593,733 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	2	8/5/2024	NON-COMPETING CONTINUATION	$593,733
														Subtotal = $593,733

Issue Date FY: 2023 ( Subtotal = $624,980 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cancer Treatment Research	000	1	8/24/2023	NEW	$624,980
														Subtotal = $624,980

Grand Total All Awards = $1,843,693

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Targeting PRC1 in leukemia

Award Number: R01CA282082

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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