# Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $488,387

## Abstract

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. To date, no effective therapies have
been approved for treating the fatal diseases. 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 of which 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 the SEC or DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading
to the pathogenesis of leukemias. We and others have recently demonstrated that ENL, a component of the
SEC and DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally
conserved YEATS domain that we identified as a reader of histone acetylation. We also found that the YEATS
domain of ENL, but not AF9, is essential for growth and survival of the MLL-rearranged leukemic cells. These
key findings strongly suggest that ENL is a promising therapeutic target for MLL-rearranged leukemias. However,
while a recently reported small-molecule inhibitor effectively blocks the interactions between the YEATS domain
of ENL/AF9 and acetylated histone H3, this ENL inhibitor has little or no effect on killing ENL-dependent MLL-
rearranged leukemia cells, failing to phenocopy the cell killing effect of ENL knockout. We hypothesize that
pharmacological degradation of ENL, instead of ENL inhibition that relies on occupancy-driven pharmacology,
will provide a novel and effective therapeutic strategy for treating MLL-rearranged leukemias. To test this
hypothesis, we propose to develop first-in-class ENL small-molecule degraders as in vivo chemical probes using
the proteolysis targeting chimera (PROTAC) technology and evaluate them in MLL-rearranged leukemia cells
and mouse models. We have generated promising preliminary results, suggesting that the proposed research is
feasible. The ENL degrader in vivo chemical probes generated in this project will not only help us test and validate
our therapeutic hypothesis, but can also be further optimized into drug candidates in the future and ultimately
translated in the clinic for MLL-rearranged leukemia patients.

## Key facts

- **NIH application ID:** 10815583
- **Project number:** 5R01CA260666-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jian Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,387
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815583

## Citation

> US National Institutes of Health, RePORTER application 10815583, Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias (5R01CA260666-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10815583. Licensed CC0.

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