François Gessier

RIPK3–MLKL–Mediated Neutrophil Death Requires Concurrent Activation of Fibroblast Activation Protein-α

Xiaoliang Wang, François Gessier, Remo Perozzo, Darko Stojkov et autres

Cytokine-primed neutrophils can undergo a nonapoptotic type of cell death using components of the necroptotic pathway, including receptor-interacting protein kinase-3 (RIPK3), mixed lineage kinase-like (MLKL) and NADPH oxidase. In this report, we provide evidence for a potential role of serine proteases in …

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Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Daniela Angst, François Gessier, Philipp Janser, Anna Vulpetti et autres

Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase …

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Design of Potent and Selective Covalent Inhibitors of Bruton’s Tyrosine Kinase Targeting an Inactive Conformation

Robert Pulz, Daniela Angst, Janet Dawson, François Gessier et autres

Bruton’s tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells …

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Front Cover: Structural States of Hdm2 and HdmX: X‐ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes (ChemMedChem 14/2019)

Joerg A. Kallen, Aude Izaac, Suzanne Chau, Emmanuelle Wirth et autres

The Front Cover shows a crystal of HdmX in a drop of mother liquor and the X-ray structures of the clinical trial compounds NVP-CGM097 and NVP-HDM201 bound to Hdm2. The article reveals key structural states of the cancer target proteins Hdm2 and …

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Structural States of Hdm2 and HdmX: X‐ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes

Joerg A. Kallen, Aude Izaac, Suzanne Chau, Emmanuelle Wirth et autres

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. …

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PP-034 Subcutaneous trastuzumab versus intravenous trastuzumab: an impact study

A Nierenberger, François Gessier, F. Forges, Xavier Simoëns

Background Trastuzumab is a monoclonal antibody used to treat HER2 positive breast cancers. Initially, only intravenous trastuzumab (IT) was available until the EMA authorised subcutaneous trastuzumab (ST) in 2013. The posology of IT depends on the patient’s weight whereas the posology of …

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Correction: A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097

Sébastien Jeay, Swann Gaulis, Stéphane Ferretti, Hans Bitter et autres

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

Philipp Holzer, Keiichi Masuya, Pascal Furet, Joerg A. Kallen et autres

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase …

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Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53–MDM2 interaction with a distinct binding mode

François Gessier, Joerg A. Kallen, Edgar Jacoby, Patrick Chêne et autres

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A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Sébastien Jeay, Swann Gaulis, Stéphane Ferretti, Hans Bitter et autres

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By …

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Author response: A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Sébastien Jeay, Swann Gaulis, Stéphane Ferretti, Hans Bitter et autres

The discovery and preclinical validation of a novel gene signature predictive for response to HDM2-targeting drug NVP-CGM097 could significantly improve the clinical response rate to all p53-HDM2 inhibitors.

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(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

Ha-Soon Choi, Paul V. Rucker, Zhicheng Wang, Yi Fan et autres

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, …

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