A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo
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ABSTRACT:
PROVIDER: PRJNA543332 | ENA |
REPOSITORIES: ENA
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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
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
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.
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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.
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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 advances in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. 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.
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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 advances in proteolysis-targeting chimeras (PROTACs) provide an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. 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.
2023-03-20 | MSV000091511 | MassIVE
Project description:High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.
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Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.
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Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.
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