Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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

PROVIDER: PRJNA899881 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

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

Project description:The signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target but successful targeting of STAT5 has proved to be difficult. We report herein the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and >6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose-schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and therapeutic potential of selective STAT5 protein depletion and inhibition in vitro and in vivo, but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

2023-01-25 | PXD037895 | Pride

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

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 |

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

| PRJNA872026 | ENA

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

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

| PRJNA917319 | ENA

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

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

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

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

Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.

2023-07-18 | GSE211758 | 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

| PRJNA543332 | ENA