Christophe Michoud
Hoffmann-La Roche
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Publication
Featured researches published by Christophe Michoud.
Journal of Medicinal Chemistry | 2013
Andrew F. Donnell; Christophe Michoud; Kenneth C. Rupert; Xiaochun Han; Douglas Aguilar; Karl B. Frank; Adrian J. Fretland; Lin Gao; Barry S. Goggin; J. Heather Hogg; Kyoungja Hong; Cheryl A. Janson; Robert Francis Kester; Norman Kong; Kang Le; Shirley Li; Weiling Liang; Louis J. Lombardo; Yan Lou; Christine Lukacs; Steven Gregory Mischke; John Anthony Moliterni; Ann Polonskaia; Andrew D. Schutt; Dave S. Solis; Anthony Specian; Robert Taylor; Martin Weisel; Stacy W. Remiszewski
XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.
Journal of Medicinal Chemistry | 2013
Robert Francis Kester; Andrew F. Donnell; Yan Lou; Stacy W. Remiszewski; Louis J. Lombardo; S Chen; N.T Le; J Lo; John Anthony Moliterni; Xiaochun Han; J.H Hogg; W Liang; Christophe Michoud; Kenneth C. Rupert; Steven Gregory Mischke; Kang Le; M Weisel; Cheryl A. Janson; Christine Lukacs; Adrian J. Fretland; K Hong; Ann Polonskaia; Lin Gao; Shirley Li; D.S Solis; D Aguilar; C Tardell; M Dvorozniak; S Tannu; E.C Lee
The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.
Bioorganic & Medicinal Chemistry Letters | 2013
Wylie Solang Palmer; Muzaffar Alam; Humberto Bartolome Arzeno; Kung-ching Chang; James Patrick Dunn; David Michael Goldstein; Leyi Gong; Bindu Goyal; Johannes C. Hermann; J. Heather Hogg; Gary Hsieh; Alam Jahangir; Cheryl Janson; Sue Jin; R. Ursula Kammlott; Andreas Kuglstatter; Christine Lukacs; Christophe Michoud; Linghao Niu; Deborah Carol Reuter; Ada Shao; Tania Silva; Teresa Alejandra Trejo-Martin; Karin Ann Stein; Yun-Chou Tan; Parcharee Tivitmahaisoon; Patricia Tran; Paul J. Wagner; Paul Weller; Shao-Yong Wu
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Bioorganic & Medicinal Chemistry Letters | 2007
Shaoqing Chen; Li Chen; Nam T. Le; Chunlin Zhao; Achyutharao Sidduri; Jian Ping Lou; Christophe Michoud; Louis Portland; Nicole Jackson; Jin-Jun Liu; Fred Konzelmann; Feng Chi; Christian Tovar; Qing Xiang; Yingsi Chen; Yang Wen; Lyubomir T. Vassilev
Archive | 2003
Yi Chen; Apostolos Dermatakis; Jin-Jun Liu; Kin-Chun Luk; Christophe Michoud; Pamela Loreen Rossman
Archive | 1999
Kin-Chun Luk; Christophe Michoud
Protein Engineering | 2000
Darin L. Steele; O. El-Kabbani; P. Dunten; L. Jack Windsor; R. Ursula Kammlott; Robert Crowther; Christophe Michoud; Jeffrey A. Engler; J.J. Birktoft
Archive | 2007
James Patrick Dunn; David Michael Goldstein; Leyi Gong; Joan Heather Hogg; Christophe Michoud; Wylie Solang Palmer; Achyutharao Sidduri; Tania Silva; Parcharee Tivitmahaisoon; Teresa Alejandra Trejo-Martin
Archive | 2006
David Robert Bolin; Christophe Michoud
Archive | 2007
David Michael Goldstein; Leyi Gong; Christophe Michoud; Wylie Solang Palmer; Achyutharao Sidduri