Christopher F. Claiborne
Millennium Pharmaceuticals
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Featured researches published by Christopher F. Claiborne.
Nature | 2009
Teresa A. Soucy; Peter G. Smith; Michael Milhollen; Allison Berger; James M. Gavin; Sharmila Adhikari; James E. Brownell; Kristin E. Burke; David P. Cardin; Stephen Critchley; Courtney Cullis; Amanda Doucette; James J. Garnsey; Jeffrey L. Gaulin; Rachel E. Gershman; Anna R. Lublinsky; Alice McDonald; Hirotake Mizutani; Usha Narayanan; Edward J. Olhava; Stephane Peluso; Mansoureh Rezaei; Michael D. Sintchak; Tina Talreja; Michael Thomas; Tary Traore; Stepan Vyskocil; Jie Yu; Julie Zhang; Lawrence R. Dick
The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin–proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
Proceedings of the National Academy of Sciences of the United States of America | 2007
Mark Manfredi; Jeffrey A. Ecsedy; Kristan Meetze; Suresh K. Balani; Olga Burenkova; Wei Chen; Katherine M. Galvin; Kara M. Hoar; Jessica Huck; Patrick J. LeRoy; Emily T. Ray; Todd B. Sells; Bradley Stringer; Stephen G. Stroud; Tricia J. Vos; Deborah R. Wysong; Mengkun Zhang; Joseph B. Bolen; Christopher F. Claiborne
Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G2/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.
Molecular Cell | 2010
James E. Brownell; Michael D. Sintchak; James M. Gavin; Hua Liao; Frank J. Bruzzese; Nancy J. Bump; Teresa A. Soucy; Michael Milhollen; Xiaofeng Yang; Anne L. Burkhardt; Jingya Ma; Huay-Keng Loke; Trupti Lingaraj; Dongyun Wu; Kristin B. Hamman; James J. Spelman; Courtney Cullis; Steven P. Langston; Stepan Vyskocil; Todd B. Sells; William D. Mallender; Irache Visiers; Ping Li; Christopher F. Claiborne; Mark Rolfe; Joseph B. Bolen; Lawrence R. Dick
The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways.
Clinical Cancer Research | 2011
Mark Manfredi; Jeffrey A. Ecsedy; Arijit Chakravarty; Lee Silverman; Mengkun Zhang; Kara M. Hoar; Stephen G. Stroud; Wei Chen; Vaishali Shinde; Jessica Huck; Deborah R. Wysong; David A. Janowick; Marc L. Hyer; Patrick J. LeRoy; Rachel E. Gershman; Matthew D. Silva; Melissa Saylor Germanos; Joseph B. Bolen; Christopher F. Claiborne; Todd B. Sells
Purpose: Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition in vivo. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays. Experimental Design: We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib in vitro and in vivo. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3′-fluoro-3′-deoxy-l-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on in vivo tumor cell proliferation. Results: Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response. Conclusions: Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors. Clin Cancer Res; 17(24); 7614–24. ©2011 AACR.
ACS Medicinal Chemistry Letters | 2015
Todd B. Sells; Ryan Chau; Jeffrey A. Ecsedy; Rachel E. Gershman; Kara M. Hoar; Jessica Huck; David A. Janowick; Vivek J. Kadambi; Patrick J. LeRoy; Matthew Stirling; Stephen G. Stroud; Tricia J. Vos; Deborah R. Wysong; Mengkun Zhang; Suresh K. Balani; Joseph B. Bolen; Mark Manfredi; Christopher F. Claiborne
The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
Molecular Cancer Therapeutics | 2011
Neil Bence; Paul Fleming; Jeff Ciavarri; Michael Milhollen; Sai M Pulukuri; Marc Hyer; Tary Traore; Jessica Huck; Derek Tou; Darshan S. Sappal; Kara Hoar; James M. Gavin; Yu Yang; James E. Brownell; Peter G. Smith; Lawrence Dick; Petter Veiby; Mark Manfredi; Christopher F. Claiborne
Millennium Pharmaceuticals, Inc. is dedicated to the discovery and development of novel oncology therapeutics in the area of protein homeostasis. Here we report the identification and characterization of compounds that target the ubiquitin activating enzymes, UBA1 and UBA6. These compounds are mechanism based inhibitors that inactivate the ubiquitin E1 enzymes by forming a ubiquitin compound adduct that remains tightly associated with the E1 adenylate binding site. Treatment of cells with these inhibitors results in cellular effects consistent with known Uba1 biology including rapid loss of E2 ubiquitin thioesters, loss of total ubiquitin conjugates, and accumulation of many ubiquitin proteasome system substrates. Following prolonged treatment, cells primarily arrest in the G2 phase of the cell cycle and ultimately undergo apoptosis. Reflecting the extensive cellular roles of ubiquitin, the compounds also impact global protein turnover, ER stress and DNA damage repair. UBA1 inhibition impairs ubiquitination of PCNA and the Fanconia Anemia protein FANCD2 leading to defective repair of UV induced DNA damage. UBA1 inhibition impacts numerous biological pathways relevant to cancer, results in apoptosis in vitro and is capable of inhibiting tumor growth in mouse xenografts in vivo. These data implicate UBA1 as a target for the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C82.
Journal of Medicinal Chemistry | 2004
Tricia J. Vos; Andrei Caracoti; Jennifer Lee Che; Mingshi Dai; Cheryl A. Farrer; Nancy Forsyth; Stacey V. Drabic; Robert A. Horlick; Diana Lamppu; David Yowe; Suresh K. Balani; Ping Li; Hang Zeng; Ingrid Joseph; Luis E. Rodriguez; Martin P. Maguire; Michael A. Patane; Christopher F. Claiborne
Archive | 2007
Christopher F. Claiborne; Stephen Critchley; Steven P. Langston; Edward J. Olhava; Stephane Peluso; Stepan Vyskocil; Irache Visiers; Hirotake Mizutani; Courtney Cullis
Archive | 2005
Christopher F. Claiborne; Lloyd J. Payne; Richard J. Boyce; Todd B. Sells; Stephen G. Stroud; Stuart Travers; Tricia J. Vos
Bioorganic & Medicinal Chemistry Letters | 2004
Thomas H. Marsilje; Jonathan B Roses; Emily F. Calderwood; Stephen G. Stroud; Nancy Forsyth; Christopher Blackburn; David Yowe; Wenyan Miao; Stacey V. Drabic; Marie D Bohane; J. Scott Daniels; Ping Li; Lijun Wu; Michael A. Patane; Christopher F. Claiborne