# Targeting the ENL YEATS domain for the development of anti-leukemia agents

> **NIH NIH R21** · TEXAS A&M UNIVERSITY · 2022 · $207,486

## Abstract

PROJECT SUMMARY/ABSTRACT
 Acute myeloid leukemia (AML) is a hematological cancer characterized by the quick proliferation and
accumulation of immature myeloid cells that are impaired to differentiate into normal blood cells. As one of the
deadliest subtypes of leukemia, AML is often driven by chromosomal translocations that fuse the multiple lineage
leukemia gene MLL1 to either of the YEATS domain-containing proteins, ENL or AF9. Recent studies have
indicated that ENL but not AF9 is essential for the maintenance of MLL-rearranged leukemia cells, making ENL
as a valuable target for the development of therapeutics for AML. The ENL YEATS domain serves a critical role
in the recognition of histone lysine acetylation in chromatin. By developing small molecules that selectively target
the ENL YEATS domain to inhibit its recognition of histone acetylation in chromatin, multiple compounds have
been identified that inhibit the growth of MLL-rearranged leukemia cells. Encouraged by this strong preliminary
study, the current application is focused on expanding the drug discovery endeavor in targeting ENL for the
development of MLL-rearranged leukemia therapeutics by pursuing three short-term specific aims. In the first
aim, NanoBRET systems will be developed for ENL and its close paralogue AF9 for the analysis of ENL inhibitors
in their cellular permeability, stability, selectivity, and drug residence time in cells. In the second aim, thorough
characterization of developed small molecule ENL inhibitors will be conducted and obtained knowledge will be
used for the development of novel inhibitors with improved potency and selectivity. In the third aim, a currently
booming drug discovery concept, proteolysis targeting chimera (PROTAC), will be applied to the ENL drug
discovery effort for the development of ENL-targeting PROTAC molecules. The success of the project will make
a number of potential MLL-rearranged leukemia therapeutics available for further preclinical and clinical
evaluations.

## Key facts

- **NIH application ID:** 10357052
- **Project number:** 1R21CA267512-01
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Wenshe Ray Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $207,486
- **Award type:** 1
- **Project period:** 2021-12-03 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357052

## Citation

> US National Institutes of Health, RePORTER application 10357052, Targeting the ENL YEATS domain for the development of anti-leukemia agents (1R21CA267512-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10357052. Licensed CC0.

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