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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217647 | GEO | 2022/12/15

REPOSITORIES: GEO

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

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Identification of Stat5 Target Genes by siRNA-mediated knockdown

Project description:STAT5A and STAT5B proteins belong to the family of signal transducers and activators of transcription. They are encoded by 2 separate genes with 91% identity in their amino acid sequences. Despite their high degree of conservation, STAT5A and STAT5B exert non-redundant functions, resulting at least in part from differences in target gene activation. To better characterize the differential contribution of STAT5A and STAT5B in gene regulation, we performed single or double knock-down of STAT5A and STAT5B using small interfering RNA. Subsequent gene expression profiling and RT-qPCR analyses of IL-3-stimulated Ba/F3-beta cells led to the identification of putative novel STAT5 target genes. Chromatin immunoprecipitation assays analyzing the corresponding gene loci identified unusual STAT5 binding sites compared to conventional STAT5 responsive elements. Some of the STAT5 targets identified are upregulated in several human cancers, suggesting that they might represent potential oncogenes in STAT5-associated malignancies. Keywords: siRNA-mediated knock-down

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Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

Project description:Two highly conserved transcription factors STAT5A and STAT5B play an identical role in the intracellular signaling pathway upon cytokine stimulation, while gene deletion experiments have revealed separable and overlapping functions of STAT5. This questions whether the phenotypic differences in the organ development observed in the individual knockout mice result from isoform-specific functions or quantitative differences in the expression levels of each STAT5 isoform among tissues. To elucidate the redundancy and isoform-specificity of STAT5 for development at molecular levels, mice carrying only a single allele of either Stat5a or Stat5b were generated. Both of these mice overcame the lethal anemia observed in Stat5ab-null mice, indicating that development of erythroid cell lineage was totally dependent on the dosage of STAT5. The blocked progression of B cell lineage at the pre-pro B cell stage in Stat5ab-/- mice was rescued in the presence of a single allele of either Stat5a or Stat5b, while the number of total B220+ cells in bone marrow was smaller in Stat5abnull/Stat5b- mice than Stat5abnull/Stat5a- mice. The paucity of alveolar progenitor cells in the Stat5ab-null mammary epithelium was rescued by a single allele of either Stat5a but not Stat5b, suggesting cell-type dependent isoform-specific function. Genome-wide gene expression analyses revealed that different steps of cell lineage progression require different gene sets which expression requires the different isoform of STAT5 in a dose-dependent manner in the mammary epithelium. Taken together, this study demonstrates that dose-dependent isoform specificity of STAT5A and STAT5B controls progression and differentiation of each cell lineage. Six days after observation of a plug, mammary tissues from three of each Stat5a-/- mice, Stat5ab+/null mice, Stat5abnull/Stat5b- and Stat5abnull/Stat5a- mice were collected, frozen in liquid nitrogen, and stored at -70 °C

2012-04-30 | E-GEOD-29045 | biostudies-arrayexpress

Impact of STAT5 dosage and binding location on genetic and biological programs activated in mouse mammary epithelium during pregnancy.

Project description:The transcription factor STAT5 has long been recognized as an important mediator of prolactin induced mammary development during pregnancy. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts different target promoters. Examination of genome-wide STAT5A, STAT5B, PolII and H3K4me3 in wild type (AABB) and Stat5a-null (BB) mammary tissues.

2012-09-18 | E-GEOD-40930 | biostudies-arrayexpress

Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

2012-05-01 | GSE29045 | GEO

RNA-seq data from wildtype, STAT5A-knockout and STAT5B-knockout BCR/ABLp185+ transformed mouse bone marrow cell lines

Project description:RNA-Seq of immortalized Stat5a-/-, Stat5b-/-, and wildtype BCR/ABLp185+ cell lines was used to identify STAT5A and STAT5B specific target genes.

2019-10-01 | GSE121246 | GEO

Essential role of STAT5 tyrosine phosphorylation in vivo

Project description:STAT5 proteins are vital for lymphocyte development and function. Tyrosine phosphorylation of a C-terminal tyrosine is the key event in cytokine activation of STAT5A and STAT5B. However, the role of STAT5 tyrosine phosphorylation has not been assessed in vivo. Here we generated Stat5a and Stat5b tyrosine mutant knock-in (KI) mice and found that these animals had greatly reduced CD8+ T cell numbers. These cells exhibited profoundly diminished proliferation in response to IL-2, correlating with greatly reduced IL-2-induced pRB and a block in the G1-->S phase transition. The mutant cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2R-beta and IL-2R-gamma. Our findings highlight that the tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling and elucidate the molecular basis for achieving an optimal mitogenic effect of IL-2 on CD8+ T cells.

2023-11-06 | MSV000093320 | MassIVE

Essential role of STAT5 tyrosine phosphorylation in vivo

2023-12-23 | MSV000093724 | MassIVE

STAT5 paralog dose governs T cell effector and regulatory function

Project description:The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains controversial. We addressed this longstanding question in primary CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Using a combination of genetic and genomic approaches, we demonstrate that, although both influence regulatory (Treg) and effector T cell responses, and control many of the same genes, they are not functionally equivalent and, in fact, only the latter is required for immunological tolerance. Differences in genomic distribution and transcriptomic output support the conclusion that STAT5B is dominant and, surprisingly, point towards relative abundance (i.e. paralog dose), rather than unique functional capabilities, as the principal distinguishing feature. Collectively, our data provide a unifying model for the discrete and redundant activities of STAT5A and STAT5B, establishing that asymmetrical expression underlies paralog specificity (or dominance) in the face of widespread structural homology.

2016-03-28 | GSE77656 | GEO

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