scholarly journals Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

2019 ◽  
Author(s):  
Sheila Dakhel ◽  
Tiziano Ongaro ◽  
Baptiste Gouyou ◽  
Mattia Matasci ◽  
Alessandra Villa ◽  
...  
Keyword(s):  
Small Molecule ◽  
Biological Effects ◽  
Clinical Stage ◽  
Selective Inhibition ◽  
Therapeutic Window ◽  
Tumor Bearing ◽  
Hemorrhagic Necrosis ◽  
Molecule Inhibitor ◽  
Selective Localization ◽  
Pro Inflammatory Cytokines

AbstractIntroductionCytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.MethodsGSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.ResultsTransient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.ConclusionsThe selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.

scholarly journals Application of high-throughput screening to identify a novel αIIb-specific small- molecule inhibitor of αIIbβ3-mediated platelet interaction with fibrinogen

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1248-1256 ◽  
Author(s):  
Robert Blue ◽  
Marta Murcia ◽  
Charles Karan ◽  
Markéta Jiroušková ◽  
Barry S. Coller
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Conformational Changes ◽  
High Throughput Screening ◽  
Metal Ion ◽  
Selective Inhibition ◽  
Docking Simulations ◽  
Fibrinogen Binding ◽  
Molecule Inhibitor ◽  
Novel Structures

AbstractSmall-molecule αIIbβ3 antagonists competitively block ligand binding by spanning between the D224 in αIIb and the MIDAS metal ion in β3. They variably induce conformational changes in the receptor, which may have undesirable consequences. To identify αIIbβ3 antagonists with novel structures, we tested 33 264 small molecules for their ability to inhibit the adhesion of washed platelets to immobilized fibrinogen at 16 μM. A total of 102 compounds demonstrated 50% or more inhibition, and one of these (compound 1, 265 g/mol) inhibited ADP-induced platelet aggregation (IC50: 13± 5 μM), the binding of soluble fibrinogen to platelets induced by mAb AP5, and the binding of soluble fibrinogen and a cyclic RGD peptide to purified αIIbβ3. Compound 1 did not affect the function of GPIb, α2β1, or the other β3 family receptor αVβ3. Molecular docking simulations suggest that compound 1 interacts with αIIb but not β3. Compound 1 induced partial exposure of an αIIb ligand-induced binding site (LIBS), but did not induce exposure of 2 β3 LIBS. Transient exposure of purified αIIbβ3 to eptifibatide, but not compound 1, enhanced fibrinogen binding (“priming”). Compound 1 provides a prototype for small molecule selective inhibition of αIIbβ3, without receptor priming, via targeting αIIb.

scholarly journals Identification of Small Molecules That Selectively Inhibit Diacylglycerol Lipase–α Activity

2013 ◽  
Vol 19 (4) ◽  
pp. 595-605 ◽  
Author(s):  
Kingsley K. Appiah ◽  
Yuval Blat ◽  
Barbara J. Robertson ◽  
Bradley C. Pearce ◽  
Donna L. Pedicord ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput Screening ◽  
Selective Inhibition ◽  
Diacylglycerol Lipase ◽  
Molecule Inhibitor ◽  
Compound Collection ◽  
Attractive Therapeutic Target ◽  
The Central Nervous System ◽  
Arachidonoyl Glycerol ◽  
Α Activity

Recent genetic evidence suggests that the diacylglycerol lipase (DAGL-α) isoform is the major biosynthetic enzyme for the most abundant endocannabinoid, 2-arachidonoyl-glycerol (2-AG), in the central nervous system. Revelation of its essential role in regulating retrograde synaptic plasticity and adult neurogenesis has made it an attractive therapeutic target. Therefore, it has become apparent that selective inhibition of DAGL-α enzyme activity with a small molecule could be a strategy for the development of novel therapies for the treatment of disease indications such as depression, anxiety, pain, and cognition. In this report, the authors present the identification of small-molecule inhibitor chemotypes of DAGL-α, which were selective (≥10-fold) against two other lipases, pancreatic lipase and monoacylglycerol lipase, via high-throughput screening of a diverse compound collection. Seven chemotypes of interest from a list of 185 structural clusters, which included 132 singletons, were initially selected for evaluation and characterization. Selection was based on potency, selectivity, and chemical tractability. One of the chemotypes, the glycine sulfonamide series, was prioritized as an initial lead for further medicinal chemistry optimization.

Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation

2017 ◽  
Vol 137 ◽  
pp. 61-80 ◽  
Author(s):  
Sarder Arifuzzaman ◽  
Amitabh Das ◽  
Sun Hwa Kim ◽  
Taeho Yoon ◽  
Young Seek Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Molecule ◽  
Selective Inhibition ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation

2012 ◽  
Vol 109 (52) ◽  
pp. 21360-21365 ◽  
Author(s):  
W. Qi ◽  
H. Chan ◽  
L. Teng ◽  
L. Li ◽  
S. Chuai ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Small Molecule ◽  
Selective Inhibition ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled

2009 ◽  
Vol 284 (24) ◽  
pp. 16256-16263 ◽  
Author(s):  
David Grandy ◽  
Jufang Shan ◽  
Xinxin Zhang ◽  
Sujata Rao ◽  
Shailaja Akunuru ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Biological Effects ◽  
Pdz Domain ◽  
Testing System ◽  
Ligand Screening ◽  
Molecule Inhibitor ◽  
Small Molecule Compound

Dishevelled (Dvl) is an essential protein in the Wnt signaling pathways; it uses its PDZ domain to transduce the Wnt signals from the membrane receptor Frizzled to downstream components. Here, we report identifying a drug-like small molecule compound through structure-based ligand screening and NMR spectroscopy and show the compound to interact at low micromolar affinity with the PDZ domain of Dvl. In a Xenopus testing system, the compound could permeate the cell membrane and block the Wnt signaling pathways. In addition, the compound inhibited Wnt signaling and reduced the levels of apoptosis in the hyaloid vessels of eye. Moreover, this compound also suppressed the growth of prostate cancer PC-3 cells. These biological effects suggest that by blocking the PDZ domain of Dvl, the compound identified in our studies effectively inhibits the Wnt signaling and thus provides a useful tool for studies dissecting the Wnt signaling pathways.

scholarly journals Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site

2016 ◽  
Vol 113 (27) ◽  
pp. 7503-7508 ◽  
Author(s):  
Monica Kasbekar ◽  
Gerhard Fischer ◽  
Bryan T. Mott ◽  
Adam Yasgar ◽  
Marko Hyvönen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Small Molecule ◽  
Conformational Changes ◽  
Fumarate Hydratase ◽  
Selective Inhibition ◽  
Small Molecule Inhibitor ◽  
Metabolic Enzyme ◽  
Regulatory Site ◽  
Allosteric Site ◽  
Molecule Inhibitor

Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-Å resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen.

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