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A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (ChIP-Seq)

ABSTRACT: A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (ChIP-Seq)

PROVIDER: PRJNA1030399 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26454006_1.fastq.gz	Fastqsanger.gz
	SRR26454006_2.fastq.gz	Fastqsanger.gz
	SRR26454007_1.fastq.gz	Fastqsanger.gz
	SRR26454007_2.fastq.gz	Fastqsanger.gz
	SRR26454008_1.fastq.gz	Fastqsanger.gz

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A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo

Project description:A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo

| PRJNA1030395 | ENA

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (ChIP-Seq)

Project description:ENL, a stoichiometric component of the Super Elongation Complex (SEC) as well as the histone H3K79 methyltransferase DOT1L complex, is involved in the regulation of transcription elongation. Loss-of-function studies of ENL highlighted an essential role for its chromatin reader YEATS domain in the progression of acute leukemia, suggesting ENL as an attractive therapeutic target for leukemia therapy. Proteolysis targeting chimeras (PROTACs), a class of new therapeutic modalities, have the potential to degrade target proteinsthrough the ubiquitin-proteasome system. PROTACs have the potential to deliver robust therapeutic effects at low doses and infrequent dosing regimens with less side-effects. Here, we designed and synthesized a serial of ENL PROTACs. Through screening by ENL degradation in human leukemia cells, we identified MS47 as a potent ENL PROTAC. MS47 efficiently and specifically degrades ENL in a concentration-dependent and time dependent manner. In line with the mechanism of action of PROTACs, proteasome inhibitors can block ENL degradation mediated by MS47. MS47 suppresses survival and growth of a panel of acute leukemia cells, and efficiently suppresses the expression of ENL target genes, including Hoxa9, Meis1, Myb and Myc. In disseminated xenograft model, MS47 significantly benefits mouse survival, inhibits leukemia cell growth in vivo. No obvious toxic effect shown in toxicity test in vivo. Modest changes occurred on normal hematopoiesis. Together, our study developed a potent ENL PROTAC for leukemia treatment.

2024-09-13 | GSE245925 | GEO

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (RNA-Seq)

2024-09-13 | GSE245926 | GEO

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (RNA-Seq)

Project description:A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (RNA-Seq)

| PRJNA1030400 | ENA

A Potent and Selective Small-Molecule STAT5 PROTAC Degrader Capable of Achieving Tumor Regression In Vivo

Project description:We have developed AK2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. To investigate the effect of STAT5A/STAT5B depletion on the transcriptome, we treated KU812 and NCO2 cells with AK2292 at 1 μM for 8 h and performed RNA-seq analysis. As a control, we treated KU812 and NCO2 cells with AK2292Me at 5 μM for 24 h for RNA-seq analysis. RNA-seq analysis revealed that AK2292 downregulates the transcriptome associated with STAT5A and STAT5B.

2022-12-15 | GSE217647 | GEO

A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression.

Project description:The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia-rearranged (MLL-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of MLL-r leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.

| S-EPMC11352836 | biostudies-literature

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo

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

2024-09-13 | GSE245927 | GEO

A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo

Project description:A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo

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A Potent and Selective Small-Molecule STAT5 PROTAC Degrader Capable of Achieving Tumor Regression In Vivo

Project description:A Potent and Selective Small-Molecule STAT5 PROTAC Degrader Capable of Achieving Tumor Regression In Vivo

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A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo

Project description:Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large cell lymphoma cell lines by inducing cell cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well tolerated dose schedules. Degradation of STAT3 protein therefore represents a promising cancer therapeutic strategy.

2019-11-11 | GSE131358 | GEO

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