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Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia

ABSTRACT: Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia

PROVIDER: PRJNA767636 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16130662.fastq.gz	Fastqsanger.gz
	SRR16130663.fastq.gz	Fastqsanger.gz
	SRR16130664.fastq.gz	Fastqsanger.gz
	SRR16130665.fastq.gz	Fastqsanger.gz
	SRR16130666.fastq.gz	Fastqsanger.gz

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Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

Project description:Acute myeloid leukemia (AML) is characterized by dysregulated transcriptional programs and these programs require support from chromatin regulators to maintain their hyperactive state. Recent studies have identified the histone acylation ‘reader’ ENL as being a critical dependency in AML, but the potential of therapeutic applications targeting this chromatin reader remains poorly understood. Here, we present a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-055, which displaces ENL from chromatin by competitively blocking the interaction of its YEATS domain with acylated histones. We show that TDI-055 treatment preferentially inhibited the proliferation of human leukemia cells harboring MLL translocations or NPM1 mutations. Through a CRISPR/Cas9 saturated mutagenesis screen, we uncovered an ENL mutant that could confer cells resistance to TDI-055, thus providing compelling proof for the on-target activity of the compound. Rapid displacement of ENL from chromatin resulted in decreased recruitment of select ENL-associated complexes and impaired RNA polymerase II elongation which, in turn, led to the suppression of critical leukemogenic gene expression programs. Finally, pharmacological inhibition of ENL in vivo led to reduced AML growth and prolonged survival in cell line and patient-derived xenograft (PDX) models. Collectively, these results provide critical evidence and mechanistic insights to establish inhibition of ENL as a potential therapeutic strategy against molecularly defined AML, laying the foundation for rapid clinical translation of this approach.

2022-10-05 | GSE185093 | GEO

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [RNA-Seq]

2022-10-05 | GSE185091 | GEO

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [RNA-Seq]

Project description:Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [RNA-Seq]

| PRJNA767641 | ENA

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

Project description:Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

| PRJNA767642 | ENA

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

Project description:The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach.SignificanceAML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.

| S-EPMC9627135 | biostudies-literature

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-05 | GSE185094 | GEO

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [ChIP-seq]

Project description:The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. Therefore, we constructed a targeted degradation system of endogenous ENL protein and investigated the roles of ENL in regulating oncogenic transcription through epigenetic reprogramming.

2024-01-18 | GSE230420 | GEO

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-seq]

2024-01-18 | GSE230421 | GEO

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [ChIP-Seq II]

2024-01-18 | GSE249553 | GEO

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]

Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.

2020-12-04 | GSE162592 | GEO

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