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Systematic Study of the Glutathione (GSH) Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution.

Adam Birkholz, David J Kopecky, Laurie P Volak, Michael D Bartberger, Yuping Chen, Chris Tegley, Tara L Arvedson, John D McCarter, Christopher H Fotsch, Victor J Cee,

A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the - and - positions of the acrylamide moiety. We find that the GSH reaction rates can generally be ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2020, :]

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The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models.

Shih-Feng Cho, Liang Lin, Lijie Xing, Yuyin Li, Kenneth Wen, Tengteng Yu, Phillip A Hsieh, Nikhil Munshi, Joachim Wahl, Katja Matthes, Matthias Friedrich, Tara Arvedson, Kenneth C Anderson, Yu-Tzu Tai,

We investigated here the novel immunomodulation and anti-multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell-dependent cellular cytotoxicity (TDCC) against MM ... Read more >>

Blood Adv (Blood advances)
[2020, 4(17):4195-4207]

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AMG 701 induces cytotoxicity of multiple myeloma cells and depletes plasma cells in cynomolgus monkeys.

Rebecca L Goldstein, Ana Goyos, Chi-Ming Li, Petra Deegen, Pamela Bogner, Alexander Sternjak, Oliver Thomas, Matthias Klinger, Joachim Wahl, Matthias Friedrich, Benno Rattel, Edwin Lamas, Xiaoshan Min, Athena Sudom, Mozhgan Farshbaf, Angela Coxon, Mercedesz Balazs, Tara Arvedson,

Multiple myeloma (MM) is a hematologic malignancy that is characterized by the accumulation of abnormal plasma cells (PCs) in the bone marrow (BM). Patient outcome may be improved with BiTE (bispecific T-cell engager) molecules, which redirect T cells to lyse tumor cells. B-cell maturation antigen (BCMA) supports PC survival and ... Read more >>

Blood Adv (Blood advances)
[2020, 4(17):4180-4194]

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Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.

Christian B Billesbølle, Caleigh M Azumaya, Rachael C Kretsch, Alexander S Powers, Shane Gonen, Simon Schneider, Tara Arvedson, Ron O Dror, Yifan Cheng, Aashish Manglik,

The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin1. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, ... Read more >>

Nature (Nature)
[2020, :]

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Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia.

Christine Karbowski, Rebecca Goldstein, Brendon Frank, Kei Kim, Chi-Ming Li, Oliver Homann, Kelly Hensley, Benjamin Brooks, Xiaoting Wang, Qinghong Yan, Rocio Hernandez, Gregor Adams, Michael Boyle, Tara Arvedson, Herve Lebrec,

Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 ... Read more >>

Toxicol. Sci. (Toxicological sciences : an official journal of the Society of Toxicology)
[2020, 177(1):94-107]

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Characterization of a Novel FLT3 BiTE Molecule for the Treatment of Acute Myeloid Leukemia.

Bettina Brauchle, Rebecca L Goldstein, Christine M Karbowski, Anja Henn, Chi-Ming Li, Veit L Bücklein, Christina Krupka, Michael C Boyle, Priya Koppikar, Sascha Haubner, Joachim Wahl, Christoph Dahlhoff, Tobias Raum, Matthew J Rardin, Christine Sastri, Dan A Rock, Michael von Bergwelt-Baildon, Brendon Frank, Klaus H Metzeler, Ryan Case, Matthias Friedrich, Mercedesz Balazs, Karsten Spiekermann, Angela Coxon, Marion Subklewe, Tara Arvedson,

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and ... Read more >>

Mol. Cancer Ther. (Molecular cancer therapeutics)
[2020, 19(9):1875-1888]

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Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.

Nicholas J Bessman, Jacques R R Mathieu, Cyril Renassia, Lei Zhou, Thomas C Fung, Keith C Fernandez, Christine Austin, Jesper B Moeller, Sara Zumerle, Sabine Louis, Sophie Vaulont, Nadim J Ajami, Harry Sokol, Gregory G Putzel, Tara Arvedson, Robbyn E Sockolow, Samira Lakhal-Littleton, Suzanne M Cloonan, Manish Arora, Carole Peyssonnaux, Gregory F Sonnenberg,

Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin ... Read more >>

Science (Science (New York, N.Y.))
[2020, 368(6487):186-189]

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Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis

Christian Billesbølle, Caleigh Azumaya, Rachael Kretsch, Alexander Powers, Shane Gonen, Simon Schneider, Tara Arvedson, Ron Dror, Yifan Cheng, Aashish Manglik,

Abstract The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin negatively regulates iron absorption and recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron ... Read more >>

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The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

Jude Canon, Karen Rex, Anne Y Saiki, Christopher Mohr, Keegan Cooke, Dhanashri Bagal, Kevin Gaida, Tyler Holt, Charles G Knutson, Neelima Koppada, Brian A Lanman, Jonathan Werner, Aaron S Rapaport, Tisha San Miguel, Roberto Ortiz, Tao Osgood, Ji-Rong Sun, Xiaochun Zhu, John D McCarter, Laurie P Volak, Brett E Houk, Marwan G Fakih, Bert H O'Neil, Timothy J Price, Gerald S Falchook, Jayesh Desai, James Kuo, Ramaswamy Govindan, David S Hong, Wenjun Ouyang, Haby Henary, Tara Arvedson, Victor J Cee, J Russell Lipford,

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency ... Read more >>

Nature (Nature)
[2019, 575(7781):217-223]

Cited: 42 times

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Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C.

Youngsook Shin, Joon Won Jeong, Ryan P Wurz, Pragathi Achanta, Tara Arvedson, Michael D Bartberger, Iain D G Campuzano, Ray Fucini, Stig K Hansen, John Ingersoll, Jeffrey S Iwig, J Russell Lipford, Vu Ma, David J Kopecky, John McCarter, Tisha San Miguel, Christopher Mohr, Sudi Sabet, Anne Y Saiki, Andrew Sawayama, Steven Sethofer, Christopher M Tegley, Laurie P Volak, Kevin Yang, Brian A Lanman, Daniel A Erlanson, Victor J Cee,

KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target ... Read more >>

ACS Med Chem Lett (ACS medicinal chemistry letters)
[2019, 10(9):1302-1308]

Cited: 2 times

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Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes.

David Haschka, Verena Petzer, Florian Kocher, Christoph Tschurtschenthaler, Benedikt Schaefer, Markus Seifert, Sieghart Sopper, Thomas Sonnweber, Clemens Feistritzer, Tara L Arvedson, Heinz Zoller, Reinhard Stauder, Igor Theurl, Guenter Weiss, Piotr Tymoszuk,

Myelomonocytic cells are critically involved in iron turnover as aged RBC recyclers. Human monocytes are divided in 3 subpopulations of classical, intermediate, and nonclassical cells, differing in inflammatory and migratory phenotype. Their functions in iron homeostasis are, however, unclear. Here, we asked whether the functional diversity of monocyte subsets translates ... Read more >>

JCI Insight (JCI insight)
[2019, 4(8):]

Cited: 2 times

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Identification of Antibody and Small Molecule Antagonists of Ferroportin-Hepcidin Interaction.

Sandra L Ross, Kaustav Biswas, James Rottman, Jennifer R Allen, Jason Long, Les P Miranda, Aaron Winters, Tara L Arvedson,

The iron exporter ferroportin and its ligand, the hormone hepcidin, control fluxes of stored and recycled iron for use in a variety of essential biochemical processes. Inflammatory disorders and malignancies are often associated with high hepcidin levels, leading to ferroportin down-regulation, iron sequestration in tissue macrophages and subsequent anemia. The ... Read more >>

Front Pharmacol (Frontiers in pharmacology)
[2017, 8:838]

Cited: 8 times

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Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing.

Sandra L Ross, Marika Sherman, Patricia L McElroy, Julie A Lofgren, Gordon Moody, Patrick A Baeuerle, Angela Coxon, Tara Arvedson,

For targets that are homogenously expressed, such as CD19 on cells of the B lymphocyte lineage, immunotherapies can be highly effective. Targeting CD19 with blinatumomab, a CD19/CD3 bispecific antibody construct (BiTE®), or with chimeric antigen receptor T cells (CAR-T) has shown great promise for treating certain CD19-positive hematological malignancies. In ... Read more >>

PLoS ONE (PloS one)
[2017, 12(8):e0183390]

Cited: 9 times

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High-Throughput Mass Spectrometric Analysis of Covalent Protein-Inhibitor Adducts for the Discovery of Irreversible Inhibitors: A Complete Workflow.

Iain D G Campuzano, Tisha San Miguel, Todd Rowe, Daniel Onea, Victor J Cee, Tara Arvedson, John D McCarter,

We have implemented a solid-phase extraction based time-of-flight mass spectrometer system in combination with novel informatics to rapidly screen and characterize the covalent binding of different irreversible inhibitors to intact proteins. This high-throughput screening platform can be used to accurately detect and quantitate the extent of formation of different covalent ... Read more >>

J Biomol Screen (Journal of biomolecular screening)
[2016, 21(2):136-144]

Cited: 5 times

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Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution.

Victor J Cee, Laurie P Volak, Yuping Chen, Michael D Bartberger, Chris Tegley, Tara Arvedson, John McCarter, Andrew S Tasker, Christopher Fotsch,

Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N-arylacrylamides independently substituted at ortho-, meta-, and ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2015, 58(23):9171-9178]

Cited: 12 times

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Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor.

Tara Arvedson, James O'Kelly, Bing-Bing Yang,

Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting ... Read more >>

BioDrugs (BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy)
[2015, 29(3):185-198]

Cited: 13 times

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Hepcidin regulation in prostate and its disruption in prostate cancer.

Lia Tesfay, Kathryn A Clausen, Jin Woo Kim, Poornima Hegde, Xiaohong Wang, Lance D Miller, Zhiyong Deng, Nicole Blanchette, Tara Arvedson, Cindy K Miranti, Jodie L Babitt, Herbert Y Lin, Donna M Peehl, Frank M Torti, Suzy V Torti,

Hepcidin is a circulating peptide hormone made by the liver that is a central regulator of systemic iron uptake and recycling. Here, we report that prostate epithelial cells also synthesize hepcidin, and that synthesis and secretion of hepcidin are markedly increased in prostate cancer cells and tissue. Prostatic hepcidin functions ... Read more >>

Cancer Res. (Cancer research)
[2015, 75(11):2254-2263]

Cited: 51 times

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IL-22 regulates iron availability in vivo through the induction of hepcidin.

Carole L Smith, Tara L Arvedson, Keegan S Cooke, Leslie J Dickmann, Carla Forte, Hongyan Li, Kimberly L Merriam, V Kristina Perry, Linh Tran, James B Rottman, Joseph R Maxwell,

Iron is a trace element important for the proper folding and function of various proteins. Physiological regulation of iron stores is of critical importance for RBC production and antimicrobial defense. Hepcidin is a key regulator of iron levels within the body. Under conditions of iron deficiency, hepcidin expression is reduced ... Read more >>

J. Immunol. (Journal of immunology (Baltimore, Md. : 1950))
[2013, 191(4):1845-1855]

Cited: 27 times

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Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT.

Sandra L Ross, Lynn Tran, Aaron Winters, Ki-Jeong Lee, Cherylene Plewa, Ian Foltz, Chadwick King, Les P Miranda, Jennifer Allen, Holger Beckman, Keegan S Cooke, Gordon Moody, Barbra J Sasu, Elizabeta Nemeth, Tomas Ganz, Graham Molineux, Tara L Arvedson,

Ferroportin is the primary means of cellular iron efflux and a key component of iron metabolism. Hepcidin regulates Fpn activity by inducing its internalization and degradation. The mechanism of internalization is reported to require JAK2 activation, phosphorylation of Fpn tyrosine residues 302 and 303, and initiation of transcription through STAT3 ... Read more >>

Cell Metab. (Cell metabolism)
[2012, 15(6):905-917]

Cited: 67 times

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The Safety Profile of Filgrastim and Pegfilgrastim

Graham Molineux, MaryAnn Foote, Tara Arvedson, Theresa A. Neumann, MaryAnn Foote,

The discovery of endogenous proteins that regulate hematopoiesis led to the identification of human granulocyte colony-stimulating factor (G-CSF). With the advent of recombinant DNA technology, it became possible to manufacture bioactive recombinant proteins for medicinal use. Since the approval of recombinant human G-CSF (rHuG-CSF), such as filgrastim in 1991 and ... Read more >>

(Twenty Years of G-CSFClinical and Nonclinical Discoveries)
[2011, :395-408]

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Serum hepcidin but not prohepcidin may be an effective marker for anemia of inflammation (AI).

Barbra J Sasu, Hongyan Li, Mark J Rose, Tara L Arvedson, George Doellgast, Graham Molineux,

Anemia in cancer patients can result from a complex interaction of numerous factors including iron deficiency, inflammation, toxicity related to therapy and effect of cancer on the marrow. Determining effective anemia treatment can therefore be complex, requiring a combination of diagnostic tests. Research on iron metabolism has highlighted the importance ... Read more >>

Blood Cells Mol. Dis. (Blood cells, molecules & diseases)
[2010, 45(3):238-245]

Cited: 20 times

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Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia.

Barbra J Sasu, Keegan S Cooke, Tara L Arvedson, Cherylene Plewa, Aaron R Ellison, Jackie Sheng, Aaron Winters, Todd Juan, Hongyan Li, C Glenn Begley, Graham Molineux,

Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in ... Read more >>

Blood (Blood)
[2010, 115(17):3616-3624]

Cited: 125 times

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Oxidative folding of hepcidin at acidic pH.

Jingwen Zhang, Stephanie Diamond, Tara Arvedson, Barbra J Sasu, Les P Miranda,

Hepcidin is a four disulfide 25-residue peptide hormone which has a central role in the regulation of iron homeostasis. To support studies on hepcidin we have sought to establish reliable and robust synthetic methods for the preparation of correctly folded materials. While correctly-folded hepcidin has good aqueous solubility, we have ... Read more >>

Biopolymers (Biopolymers)
[2010, 94(2):257-264]

Cited: 12 times

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