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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198280 | GEO | 2022/09/09

REPOSITORIES: GEO

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

Project description:Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined "functional hotspots". Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here, we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. A Hybrid capture assay reveals resistance-conferring mutations after degrader treatment. 29 putative target genes were selected to be sequenced. Target gene enrichment from gDNA of treated cells was performed, followed by amplification and sequencing to identify mutations.

2022-09-09 | GSE198279 | GEO

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

Project description:Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined "functional hotspots". Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here, deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets and validated hotspots mutated in patients that relapse from degrader treatment.

2022-09-09 | GSE198278 | GEO

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

Project description:Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

Project description:Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

Project description:Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

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Chemical Genetics of TOR Identifies an SCF Family E3 Ubiquitin Ligase Inhibitor

Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyper-activation of the mTOR pathway in human cancers, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based high-throughput chemical genetic screen to identify small-molecule enhancers of rapamycin (SMERs) and used whole genome expression analysis to identify their mechanisms of action. This SuperSeries is composed of the following subset Series: GSE22270: Expression data from Saccharomyces cerevisiae Met30 temperature-sensitive strain GSE22271: Expression data from Saccharomyces cerevisiae temperature-sensitive strains specific for SCF core components (Skp1, Cullin (Cdc53), E2 enzyme (Cdc34)) and the F-box protein Cdc4. Refer to individual Series

2011-06-30 | E-GEOD-22272 | biostudies-arrayexpress

Chemical Genetics of TOR Identifies an SCF Family E3 Ubiquitin Ligase Inhibitor

2011-06-30 | GSE22272 | GEO

PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective.

Project description:Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase which effectively degrades tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt the MDM2-p53 binding have been discovered and developed. Given that the MDM2-p53 forms auto-regulatory loop in which p53 is a substrate of MDM2 for targeted degradation, while MDM2 is a p53 target for transcriptional upregulation, these MDM2 inhibitors have limited efficacy due to p53 degradation by accumulated MDM2 upon rapid in vivo clearance of the MDM2 inhibitors. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Some of MDM2 inhibitors developed in the past two decades have been used in PROTAC technology for two applications: 1) as component 1 to bind with endogenous MDM2 as a target for PROTAC-based degradation of MDM2; and 2) as component 2 to bind with endogenous MDM2 as a PROTAC E3 ligand for PROTAC-based degradation of other oncogenic proteins. In this review, we summarize current progress in the discovery and development of MDM2-based PROTAC drugs with future perspectives and challenges for their applications in effective treatment of human cancer.

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Design, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands.

Project description:Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).

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Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase.

Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyperactivation of the mammalian TOR (mTOR) pathway in human cancers, strategies to enhance TOR pathway inhibition are needed. We used a yeast-based screen to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor (SMER3) of the Skp1-Cullin-F-box (SCF)(Met30) ubiquitin ligase, a member of the SCF E3-ligase family, which regulates diverse cellular processes including transcription, cell-cycle control and immune response. We show here that SMER3 inhibits SCF(Met30) in vivo and in vitro, but not the closely related SCF(Cdc4). Furthermore, we demonstrate that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and show evidence for SMER3 directly binding to Met30. Our results show that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes.

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