Yannick Aimé Eddy Ligny
Johnson & Johnson Pharmaceutical Research and Development
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Featured researches published by Yannick Aimé Eddy Ligny.
Bioorganic & Medicinal Chemistry Letters | 2003
Patrick Angibaud; Xavier Bourdrez; Ann Devine; David End; Eddy Jean Edgard Freyne; Yannick Aimé Eddy Ligny; Philippe Muller; Geert Mannens; Isabelle Pilatte; Virginie Sophie Poncelet; Stacy Skrzat; Gerda Smets; Jacky Van Dun; Pieter Van Remoortere; Marc Venet; W. Wouters
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
Cancer Research | 2017
Matthias Versele; Lut Janssen; Tamara Geerts; Wim Floren; Boudewijn Janssens; Hillary Millar; Edgar Jacoby; Gerhard Max Gross; Yannick Aimé Eddy Ligny; Yvan Simonnet; Nathalie Amblard; Olivier Querolle; Imre Csoka; Virginie Sophie Poncelet; Virginie Tronel; Sophie Nocquet-Thibault; Lieven Meerpoel; James R. Edwards; Marc Salvati; Sriram Balasubramanian; Laurie Lenox; Charles P. Theuer; Ricardo M. Attar; Ian Stansfield
Enhanced NF-kB signaling is a hallmark of aggressive lymphoid malignancies, including multiple myeloma (MM), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). Non-canonical NF-kB signaling involves NIK-dependent activation of IKKα, which triggers nuclear accumulation of p52/RelB heterodimers. NIK is a highly unstable protein and degradation is mediated by a ubiquitin ligase complex consisting of TRAF2, TRAF3 and c-IAP1/2 (encoded by BIRC2/3). In a subset of MM, NIK is stabilized by mutations in NIK, TRAF2/3 or BIRC2/3 (Annunziata et al./Keats et al., Canc. Cell 2007). Similar activating mutations in the non-canonical NF-kB signaling pathway were recently found in ibrutinib-refractory MCL cell lines (Rahal et al., Nat. Med. 2014), and in DLBCL (Zhang et al., Cell Rep. 2015). In many other cases of B-cell malignancies, NIK is stabilized by high level expression of the upstream TNF receptors (BAFFR, CD40, LTβR) or high abundance of their ligands in the bone marrow or the lymph nodes. To date, bioavailable NIK inhibitors have not been reported, and it has remained unclear whether NIK inhibitors are effective and tolerated in mouse models of B-cell malignancies associated with activation of NIK. Here, we report for the first time on a potent orally bioavailable NIK kinase inhibitor, TRC694. TRC694 selectively inhibits NIK enzymatic activity, translating into inhibition of phospho-IKKα in NIK and in TRAF3 mutant cell lines with single digit nM IC50. TRC694 prevents nuclear accumulation of p52/RelB (but not canonical NF-kB) and represses the associated NF-kB gene program selectively in MM cell lines with genetic activation of the non-canonical NF-kB pathway. Proliferation of NIK translocated, TRAF3 or BIRC3 mutant MM cell lines is inhibited by low nM concentrations of TRC694, whereas MM cell lines which lack genetic activation of non-canonical NF-kB are much less sensitive to TRC694. Consistently, elevated expression of a previously described 11-gene NFkB signature in MM (Annunziata et al., Canc. Cell 2007) is predictive of sensitivity to TRC694 in a 21-MM cell line panel. A single, oral dose of 10 to 40 mg/kg of TRC694 to mice bearing a NIK-translocated MM tumor (JJN-3), was sufficient to inhibit phospho-IKKα and repress P52-mediated transcription of NFkB regulated genes in the tumors. Consistently, once-daily, oral dosing of TRC694 to mice bearing subcutaneous NIK translocated (JJN-3) or TRAF3 (RPMI-8226, MM.1S) mutant MM tumors, completely inhibits growth of these tumors at doses of 10 to 40 mg/kg, with no signs of toxicities. In conclusion, TRC694 is a first-in-class orally bioavailable NIK kinase inhibitor, and provides the first opportunity to test the clinical relevance of non-canonical NF-kB inhibition in aggressive lymphoid malignancies. Citation Format: Matthias Versele, Lut Janssen, Tamara Geerts, Wim Floren, Boudewijn Janssens, Hillary Millar, Edgar Jacoby, Gerhard Gross, Yannick Ligny, Yvan Simonnet, Nathalie Amblard, Olivier Querolle, Imre Csoka, Virginie Poncelet, Virginie Tronel, Sophie Nocquet-Thibault, Lieven Meerpoel, James Edwards, Marc Salvati, Sriram Balasubramanian, Laurie Lenox, Charles Theuer, Ricardo Attar, Ian Stansfield. Inhibition of NF-kB inducing kinase (NIK) selectively abrogates NIK and TRAF3 mutant multiple myeloma tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4199. doi:10.1158/1538-7445.AM2017-4199
Archive | 1998
Marc Gaston Venet; Patrick René Angibaud; Yannick Aimé Eddy Ligny; Virginie Sophie Poncelet; Gerard Charles Sanz
European Journal of Organic Chemistry | 2004
Patrick Angibaud; Marc Gaston Venet; Walter Ferdinand Maria Filliers; Rudy Laurent Maria Broeckx; Yannick Aimé Eddy Ligny; Philippe Muller; Virginie Sophie Poncelet; Dave W. End
Bioorganic & Medicinal Chemistry Letters | 2003
Patrick Angibaud; Xavier Bourdrez; David William End; Eddy Jean Edgard Freyne; Michel Janicot; Patricia Lezouret; Yannick Aimé Eddy Ligny; Geert Mannens; Siegrid Damsch; Laurence Mevellec; Christophe Meyer; Philippe Muller; Isabelle Pilatte; Virginie Sophie Poncelet; Bruno Roux; Gerda Smets; Jacky Van Dun; Pieter Van Remoortere; Marc Venet; Walter Wouters
Cancer Research | 2008
Janine Arts; Martin John Page; Annemie Francine Valckx; Christine Blattner; R. Kulikov; Wim Floren; Luc Van Nuffel; Lut Janssen; Peter H. King; Stefan Masure; Karine Smans; Peter Verhasselt; Hinrich Goehlmann; Yannick Aimé Eddy Ligny; Delphine Yvonne Raymonde Lardeau; Imre Csoka; Luc Andries; Dirk Brehmer; Eddy Jean Edgard Freyne; Eugen Leo; Michel Janicot; Christophe Meyer; Jean Fernand Armand Lacrampe; Bruno Schoentjes
Archive | 2011
Patrick René Angibaud; Valerio Berdini; Gilbert Ebai Besong; Christopher Charles Frederick Hamlett; Yannick Aimé Eddy Ligny; Christopher William Murray; Gordon Saxty; Steven John Woodhead
Archive | 2011
Valerio Berdini; Gordon Saxty; Christopher William Murray; Gilbert Ebai Besong; Christopher Charles Frederick Hamlett; Steven John Woodhead; Yannick Aimé Eddy Ligny; Patrick René Angibaud
Archive | 2011
Valerio Berdini; Gordon Saxty; Christopher William Murray; Gilbert Ebai Besong; Christopher Charles Frederick Hamlett; Steven John Woodhead; Yannick Aimé Eddy Ligny; Patrick René Angibaud
Archive | 2010
Gordon Saxty; Valerio Berdini; Christopher William Murray; Eddy Jean Edgard Freyne; Yannick Aimé Eddy Ligny; Pascal Bonnet; Berthold Wroblowski; Alexandra Papanikos