scholarly journals The small molecule PSSM0332 disassociates the CRL4ADCAF8 E3 ligase complex to decrease the ubiquitination of NcoR1 and inhibit the inflammatory response in a mouse sepsis-induced myocardial dysfunction model

2020 ◽  
Vol 16 (15) ◽  
pp. 2974-2988
Author(s):  
Qingyun Peng ◽  
Huifen Xu ◽  
Mingbing Xiao ◽  
Linhua Wang
Keyword(s):  
Inflammatory Response ◽  
Small Molecule ◽  
Myocardial Dysfunction ◽  
E3 Ligase

scholarly journals INH14, a Small-Molecule Urea Derivative, Inhibits the IKKα/β-Dependent TLR Inflammatory Response

ChemBioChem ◽  
2019 ◽  
Vol 20 (5) ◽  
pp. 710-717 ◽  
Author(s):  
Meinrad Drexel ◽  
Johannes Kirchmair ◽  
Sandra Santos-Sierra
Keyword(s):  
Inflammatory Response ◽  
Small Molecule ◽  
Urea Derivative

scholarly journals Natural small molecule FMHM inhibits lipopolysaccharide-induced inflammatory response by promoting TRAF6 degradation via K48-linked polyubiquitination

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Ke-Wu Zeng ◽  
Li-Xi Liao ◽  
Hai-Ning Lv ◽  
Fang-Jiao Song ◽  
Qian Yu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Small Molecule

Abstract 50: Small molecule Ring1B-Bmi1 inhibitor attenuates PRC1 E3 ligase activity and targets leukemia stem cells self-renewal

2017 ◽  
Author(s):  
Shirish Shukla ◽  
Felicia Gray ◽  
Weijiang Ying ◽  
Hyoje Cho ◽  
Qingjie Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Small Molecule ◽  
E3 Ligase ◽  
Leukemia Stem Cells ◽  
Self Renewal

scholarly journals Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyle R. Simonetta ◽  
Joshua Taygerly ◽  
Kathleen Boyle ◽  
Stephen E. Basham ◽  
Chris Padovani ◽  
...  
Keyword(s):  
Small Molecule ◽  
E3 Ligase ◽  
Substrate Interaction ◽  
Small Molecule Enhancers

Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion

1997 ◽  
Vol 185 (4) ◽  
pp. 365-372 ◽  
Author(s):  
J PALMAVARGAS ◽  
L TOLEDOPEREYRA ◽  
R DEAN ◽  
J HARKEMA ◽  
R DIXON ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Small Molecule ◽  
Ischemia And Reperfusion

Interleukin-27 attenuates myocardial injury after ischemia-reperfusion through down-regulation of inflammatory response

2021 ◽  
Vol 9 (1) ◽  
pp. 62-75
Author(s):  
Mai HN ◽  
Lee YS
Keyword(s):  
Inflammatory Response ◽  
Ventricular Function ◽  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Mice Model ◽  
Down Regulation ◽  
Stat Pathway

The proinflammatory cytokines may mediate myocardial dysfunction associated with myocardial injury and inflammatory response is an important process during the pathogenesis of myocardial I/R injury. IL-27, this cytokine is mainly produced by cells of myeloid origin such as monocytes, macrophages, dendritic cells, and microglial cells, in response to stimuli acting through Toll-like receptors. The objective of present study is to assess whether IL-27 can improve ventricular function after myocardial ischemia by down-regulation of inflammatory response. The results demonstrated that the IL-27 markedly attenuated Left Ventricular Function (LVF) in mice model, and reduced plasma level of cTn-I as marker of cardiac injury. Moreover, the IL-27 was associated with up-regulation in both chemokine and cytokines expression following I/R, through down-regulation of activation of JAK/STAT pathway.

scholarly journals An In Vivo CRISPR Screening Platform to Identify New Therapeutic Targets in AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 266-266
Author(s):  
Shan Lin ◽  
Clement Larrue ◽  
Nastassja K. Scheidegger ◽  
Bo Kyung A. Seong ◽  
Neekesh V Dharia ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Large Scale ◽  
E3 Ligase ◽  
Functional Genomic ◽  
Dependent Manner ◽  
Pdx Model ◽  
Pdx Models

Abstract First-generation, large-scale functional genomic screens have revealed hundreds of potential genetic vulnerabilities in acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because these large-scale genetic screens were primarily performed in vitro in established AML cell lines, their translational relevance has been debated. Therefore, we established a protocol for CRISPR screening in orthotopic xenograft models of human AML, including patient-derived-xenograft (PDX) models that are tractable for CRISPR-editing. We first defined experimental conditions necessary for an optimal in vivo screen via barcoding experiments. We determined that sub-lethal irradiation was necessary for improved barcode representation in bone marrow and to reduce mouse-to-mouse variation. Moreover, it was critical to combine samples from multiple mice to achieve complete in vivo library representation. Next, using the Broad DepMap and other publicly available functional genomic screen data, we identified 200 genes that were stronger dependencies in AML cell lines compared to all other cancer types screened. Using this list, we created a secondary library and performed parallel in vivo and in vitro screens using the MV4-11 and U937 cell lines and a PDX model. In vitro and in vivo hits were surprisingly well correlated, although a modest number of targets did not score well in vivo. Notably, dependencies identified across AML cell line models were strongly recapitulated in the PDX model, validating the application of AML cell lines for dependency discovery. Our in vivo screens nominated the mitochondria-localized RING-type ubiquitin E3 ligase MARCH5 as a potential therapeutic target in AML. Using CRISPR, we first validated this in vitro dependency on MARCH5 and determined that MARCH5 is a critical guardian to prevent apoptosis in AML. MARCH5 depletion activates the canonical mitochondrial apoptosis pathway in a BAX/BAK1-dependent manner. Multiple genome-wide screens revealed that a dependency on MARCH5 is strongly correlated with a dependency on MCL1, but not other anti-apoptotic BCL2-family members, across the AML cell lines in the screen. As observed with MCL1 inhibition, MARCH5 depletion sensitized AML cells to venetoclax, a BCL2-specific inhibitor FDA-approved in combination with a hypomethylating agent for the treatment of older adults with AML. Importantly, MARCH5 depletion diminished the venetoclax resistance induced by MCL1 overexpression but not that caused by BCLXL overexpression. Altogether, these results suggest that MARCH5 is required for maintaining MCL1 activity specifically. Since there are no small molecule inhibitors directed against MARCH5, we deployed a dTAG system as an approximation of pharmacological inhibition. This approach uses a hetero-bifunctional small molecule that binds the FKBP12 F36V-fused MARCH5 and the E3 ligase VHL, leading to the ubiquitination and proteasome-mediated degradation of the fusion protein. dTAG-MARCH5 cells were established via deleting endogenous MARCH5 by CRISPR and expressing exogenous FKBP-tagged MARCH5 protein. MARCH5 degradation with the dTAG molecule dTAG V-1 markedly impaired cell growth in vitro. Additionally, we demonstrated the utility of dTAG system in vivo using a PDX model. The combination treatment of dTAG V-1 and venetoclax elicited a much stronger anti-leukemic effect compared to the treatment with only venetoclax or dTAG V-1, further highlighting MARCH5 as a promising synergistic target for enhancing the efficacy of venetoclax in AML. Taken together, our in vivo screening approach, coupled with CRISPR-competent PDX models and dTAG-directed protein degradation, constitute a useful platform for prioritizing AML targets emerging from in vitro screens to serve as the starting point for therapy development. Disclosures Dharia: Genentech: Current Employment. Piccioni: Merck Research Laboratories: Current Employment. Stegmaier: Bristol Myers Squibb: Consultancy; KronosBio: Consultancy; AstraZeneca: Consultancy; Auron Therapeutics: Consultancy, Current equity holder in publicly-traded company; Novartis: Research Funding.

QSAR modeling and in silico design of small-molecule inhibitors targeting the interaction between E3 ligase VHL and HIF-1 $$\alpha $$ α

2017 ◽  
Vol 21 (3) ◽  
pp. 719-739
Author(s):  
Jing Pan ◽  
Yanmin Zhang ◽  
Ting Ran ◽  
Anyang Xu ◽  
Xin Qiao ◽  
...  
Keyword(s):  
Small Molecule ◽  
In Silico ◽  
Small Molecule Inhibitors ◽  
E3 Ligase ◽  
Qsar Modeling ◽  
In Silico Design
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