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BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

ABSTRACT: BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

PROVIDER: PRJNA917319 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22951370.fastq.gz	Fastqsanger.gz
	SRR22951371.fastq.gz	Fastqsanger.gz
	SRR22951372.fastq.gz	Fastqsanger.gz
	SRR22951373.fastq.gz	Fastqsanger.gz
	SRR22951374.fastq.gz	Fastqsanger.gz

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Similar Datasets

BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

Project description:We demonstrated that secondary Plasma Cell Leukemia, addicted to BCLXL, a small but a very challenging group of patients, could benefit from DT2216, underpinning its clinical evaluation.

2024-01-30 | GSE222016 | GEO

BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival.

Project description:Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. Accordingly, BH3 profiling of 2 sPCL sensitive to BCLXL inhibition confirmed their high BCLXL primed profile. While targeting BCLXL using BH3 mimetics induces platelets on-target drug toxicity, the recent development of DT2216, a clinical-stage BCLXL proteolysis targeting chimera PROTAC compound, provides an alternative strategy to target BCLXL. Indeed, DT2216 specifically degrades BCLXL via VHL E3 ligase, without inducing thrombocytopenia. We demonstrated in human myeloma cell lines and sPCL that sensitivity to DT2216 strongly correlated with the sensitivity to A1155463. Interestingly, we showed that low doses of DT2216 (nM range) were sufficient to specifically degrade BCLXL after 48 hours of treatment, consistent with VHL expression, in all cell lines but irrespectively to DT2216 sensitivity. In myeloma cells, DT2216 induced apoptotic cell death and triggered BAX and BAK activation. In conclusion, our study demonstrated that patients with sPCL addicted to BCLXL, a small but a very challenging group, could potentially receive therapeutic benefit from DT2216. Clinical trials of DT2216 in this subset of sPCL patients are warranted.

| S-EPMC10393035 | biostudies-literature

Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

Project description:Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

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Discovery of 180055 as a PROTAC degrader for Treating Cancers

Project description:PARP1 is an abundant nuclear protein that is involved in a number of biological processes linked to cellular stress responses. PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (PARP1 catalytic inhibition and PARP1 trapping). In this work we discovered a PROTAC degrader of PARP1 -180055, which uncoupled PARP1 trapping and inhibition. Moreover, 180055 has great potential for treating cancers.

2023-05-18 | PXD042311 |

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [ATAC-Seq]

Project description:This study profiles chromatin accessibility, gene expresison, transcription factor binding, and three-dimensional DNA-DNA contact changes upon rapid SWI/SNF ATPase inactivation in prostate cancer cells. SWI/SNF ATPases activity was disabled using a novel PROTAC degrader compound targeting the SMARCA2, SMARCA4 and PBRM1 subunits of the SWI/SNF remodeling complex.

2021-10-28 | GSE171584 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [RNA-Seq]

2021-10-28 | GSE171523 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [HiChIP-Seq]

2021-10-28 | GSE171591 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [ChIP-Seq]

2021-10-28 | GSE171589 | GEO

HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

Project description:HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

| PRJNA947763 | ENA

Selective PROTAC-mediated degradation and shRNA-driven knockdown of SMARCA2 in HCC2302 lung adenocarcinoma cells

Project description:SMARCA2 and SMARCA4 are mutually-exclusive, core catalytic subunits for the chromatin remodeling SWI/SNF complex. Mutations in SMARCA4 are common in lung adenocarcinoma and have shown synthetic lethality with loss of SMARCA2 loss of function. The purpose of this project is to answer questions related to the in vivo [mouse xenograft] efficacy of A947, a SMARCA2 degrader. The study involves in vitro versus in vivo comparisons of drug activity, in addition to genetic manipulation of the target. Model system: HCC2302 (RRID:CVCL_V636); Model origin: Lung Adenocarcinoma; Perturbation: A947 (VHL-PROTAC-based degrader)

2022-06-13 | GSE205542 | GEO

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