Eric Vangrevelinghe

Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement

Juraj Velcicky, Jean‐Baptiste Langlois, Michael Wright, Philipp Janser et autres

Abstract NLRP3 is a molecular sensor present in innate immune cells which recognizes a variety of danger signals such as MSU, ATP, or Aβ. Upon activation, it seeds a protein complex termed the inflammasome, which leads to secretion of the proinflammatory cytokines …

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Discovery and Optimization of Selective Inhibitors of Large Tumor Suppressor Kinases LATS1 and 2 for In Vivo Investigation of the Hippo-YAP Pathway in Tissue Regeneration

Kenji Namoto, Eric Vangrevelinghe, Rainer Machauer, Dirk Behnke et autres

Large Tumor Suppressor kinases LATS1 and 2 (LATS1/2) are serine/threonine kinases and core regulators of the Hippo-YAP pathway. Inhibition of LATS1/2 promotes nuclear translocation of nonphosphorylated YAP, thereby initiating a downstream cascade promoting cell proliferation. We set out to investigate the potential …

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Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome

Angela Mackay, Juraj Velcicky, Nina Gommermann, Henri Mattes et autres

Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked …

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Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration

Jean‐Baptiste Langlois, Silke Brenneisen, Stephane Rodde, Eric Vangrevelinghe et autres

Osteoarthritis (OA) is a chronic and degenerative joint disease affecting more than 500 million patients worldwide with no disease-modifying treatment approved to date. Several publications report on the transforming growth factor β-activated kinase 1 (TAK1) as a potential molecular target for OA, …

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NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo

Kenji Namoto, Clara Baader, Vanessa Orsini, Alexandro Landshammer et autres

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Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors

Juraj Velcicky, Philipp Janser, Nina Gommermann, Silke Brenneisen et autres

NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1β and IL-18, as well as cleavage of Gasdermin- d and …

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Design of a Supersoft Topical JAK Inhibitor, Which Is Effective in Human Skin but Rapidly Deactivated in Blood

Gebhard Thoma, Odile Decoret, Eric Vangrevelinghe, Markus Trunzer et autres

We describe the discovery and characterization of the supersoft topical JAK inhibitor 3(R), which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester 3(R) is rapidly hydrolyzed ( t 1/2 ∼ 6 …

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Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation

Gebhard Thoma, Eric Vangrevelinghe, Alexandre Luneau, Philippe Piéchon et autres

We present a novel concept for the design of supersoft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3 . Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing …

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Data from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Rita Andraos, Zhiyan Qian, Débora Bonenfant, Joëlle Rubert et autres

Abstract Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can …

Supplementary Table S3 from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Rita Andraos, Zhiyan Qian, Débora Bonenfant, Joëlle Rubert et autres

PDF file - 72K, X-ray crystallographic data collection and refinement statistics. Diffraction data were collected at the Swiss Light Source (beamline X10SA). Raw diffraction data were processed and scaled with the XDS/XSCALE software package. The program BUSTER was used for structure refinement …

Supplementary Table S1 from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Rita Andraos, Zhiyan Qian, Débora Bonenfant, Joëlle Rubert et autres

PDF file - 11K, Activity of NVP-BBT594 in biochemical and cell-based assays. The IC50 (mean of two experiments) of NVP-BBT594 on the JAK2 kinase was determined in a biochemical kinase assay with the active enzyme. Half-maximal growth inhibition (GI50,) of NVP-BBT594 was …

Supplementary Figures, Methods, and References from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Rita Andraos, Zhiyan Qian, Débora Bonenfant, Joëlle Rubert et autres

PDF file - 841K, Supplementary Figures S1-S6; legends for Supplementary Tables S1-S3; Supplementary Methods describing RNA interference, generation of Ba/F3 cell lines, site-directed mutagenesis, transient transfection, inhibition of cellular ATP production, proliferation assays, enzymatic assays with JAK2 JH1, purification of tyrosine phosporylated …

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