Linda O. Elliott
Genentech
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Publication
Featured researches published by Linda O. Elliott.
Cell | 2007
Eugene Varfolomeev; John W. Blankenship; Sarah M. Wayson; Anna V. Fedorova; Nobuhiko Kayagaki; Parie Garg; Kerry Zobel; Jasmin N. Dynek; Linda O. Elliott; Heidi J.A. Wallweber; John A. Flygare; Wayne J. Fairbrother; Kurt Deshayes; Vishva M. Dixit; Domagoj Vucic
Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.
ACS Chemical Biology | 2009
Chudi Ndubaku; Eugene Varfolomeev; Lan Wang; Kerry Zobel; Kevin Lau; Linda O. Elliott; Brigitte Maurer; Anna V. Fedorova; Jasmin N. Dynek; Michael F. T. Koehler; Sarah G. Hymowitz; Vickie Tsui; Kurt Deshayes; Wayne J. Fairbrother; John A. Flygare; Domagoj Vucic
The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their functional characterization as activators of apoptosis in tumor cells. Although capable of inducing cell death and preventing clonogenic survival, c-IAP-selective antagonists are significantly less potent in promoting apoptosis when compared to pan-selective compounds. However, both pan-IAP- and c-IAP-selective antagonists stimulate c-IAP1 and c-IAP2 degradation and activation of NF-kappaB pathways with comparable potencies. Therefore, although compounds that specifically target c-IAP1 and c-IAP2 are capable of inducing apoptosis, antagonism of the c-IAP proteins and XIAP is required for efficient induction of cancer cell death by IAP antagonists.
Journal of Medicinal Chemistry | 2009
Fred E. Cohen; Bruno Alicke; Linda O. Elliott; John A. Flygare; Tatiana Goncharov; Stephen F. Keteltas; Matthew C. Franklin; Stacy Frankovitz; Jean-Philippe Stephan; Vickie Tsui; Domagoj Vucic; Harvey Wong; Wayne J. Fairbrother
A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.
Bioorganic & Medicinal Chemistry Letters | 2010
Frederick Cohen; Michael F. T. Koehler; Philippe Bergeron; Linda O. Elliott; John A. Flygare; Matthew C. Franklin; Lewis J. Gazzard; Stephen F. Keteltas; Kevin Lau; Cuong Ly; Vickie Tsui; Wayne J. Fairbrother
A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have K(i)s of 20-30 nM against ML-IAP and 50-60 nM against XIAP-BIR3.
Journal of Biomolecular Screening | 2012
Yichin Liu; Maureen Beresini; Adam R. Johnson; Robert Mintzer; Kinjalkumar Shah; Kevin Clark; Stephen Schmidt; Cristina Lewis; Marya Liimatta; Linda O. Elliott; Amy Gustafson; Christopher E. Heise
Identifying chemical lead matter by high-throughput screening (HTS) has been a common practice in early stage drug discovery. Evolution of small-molecule library composition to include more drug-like molecules with desirable physical chemical properties combined with improving assay technologies has vastly enhanced the capability of HTS. However, HTS campaigns can still be plagued by false positives arising from nonspecific inhibitors. The generation of assay-ready plates has permitted an incremental advancement to the speed and efficiency of HTS but has the potential to enhance the occurrence of nonspecific inhibitors. A subtle change in the order of reagent addition to the assay-ready plates can greatly alleviate false-positive inhibition. Our case studies with six different kinase and protease targets reveal that this type of inhibition affects targets regardless of enzyme class and is unpredictable based on protein construct or inhibitor chemical scaffold. These case studies support a model where a diversity set of compounds should be tested first for hit rates as a function of order of addition, carrier protein, and relevant mechanistic studies prior to launch of the HTS campaign.
ACS Chemical Biology | 2006
Kerry Zobel; Lan Wang; Eugene Varfolomeev; Matthew C. Franklin; Linda O. Elliott; Heidi J.A. Wallweber; David C. Okawa; John A. Flygare; Domagoj Vucic; Wayne J. Fairbrother; Kurt Deshayes
Biochemical Journal | 2005
Domagoj Vucic; Matthew C. Franklin; Heidi J.A. Wallweber; Kanad Das; Brendan P. Eckelman; Hwain Shin; Linda O. Elliott; Saloumeh Kadkhodayan; Kurt Deshayes; Guy S. Salvesen; Wayne J. Fairbrother
Biochemistry | 2003
Matthew C. Franklin; Saloumeh Kadkhodayan; Heidi Ackerly; Daniela Alexandru; Mark D. Distefano; Linda O. Elliott; John A. Flygare; Grace Mausisa; David C. Okawa; Danny Ong; Domagoj Vucic; Kurt Deshayes; Wayne J. Fairbrother
Journal of Biological Chemistry | 2005
Alan G. Olivero; Charles Eigenbrot; Richard Goldsmith; Kirk Robarge; Dean R. Artis; John A. Flygare; Thomas E. Rawson; Daniel P. Sutherlin; Saloumeh Kadkhodayan; Maureen Beresini; Linda O. Elliott; Geralyn G. DeGuzman; David Banner; Mark Ultsch; Ulla M. Marzec; Stephen R. Hanson; Canio J. Refino; Stuart Bunting; Daniel Kirchhofer
Assay and Drug Development Technologies | 2007
Saloumeh Kadkhodayan; Linda O. Elliott; Grace Mausisa; Heidi J.A. Wallweber; Kurt Deshayes; Bainian Feng; Wayne J. Fairbrother