Benjamin J. Dugan
Cephalon
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Publication
Featured researches published by Benjamin J. Dugan.
Journal of Immunology | 2011
Lily D. Lu; Kristine L. Stump; Nate H. Wallace; Pawel Dobrzanski; Cynthia Serdikoff; Diane E. Gingrich; Benjamin J. Dugan; Thelma S. Angeles; Mark S. Albom; Jennifer L. Mason; Mark A. Ator; Bruce D. Dorsey; Bruce Ruggeri; Matthew M. Seavey
Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC50 = 1.3 nM; JAK3 enzyme IC50/JAK2 enzyme IC50 = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138+ plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.
Bioorganic & Medicinal Chemistry Letters | 2011
Eugen F. Mesaros; Jason P. Burke; Jonathan Parrish; Benjamin J. Dugan; Andrew V. Anzalone; Thelma S. Angeles; Mark S. Albom; Lisa D. Aimone; Matthew R. Quail; Weihua Wan; Lihui Lu; Zeqi Huang; Mark A. Ator; Bruce Ruggeri; Mangeng Cheng; Gregory R. Ott; Bruce D. Dorsey
The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
Journal of Medicinal Chemistry | 2012
Benjamin J. Dugan; Diane E. Gingrich; Eugen F. Mesaros; Karen L. Milkiewicz; Matthew A. Curry; Allison L. Zulli; Pawel Dobrzanski; Cynthia Serdikoff; Mahfuza Jan; Thelma S. Angeles; Mark S. Albom; Jennifer L. Mason; Lisa D. Aimone; Sheryl L. Meyer; Zeqi Huang; Kevin J. Wells-Knecht; Mark A. Ator; Bruce Ruggeri; Bruce D. Dorsey
Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
Archive | 2007
Gulzar Ahmed; Adolph C. Bohnstedt; Henry J. Breslin; Jason P. Burke; Matthew A. Curry; James L. Diebold; Bruce D. Dorsey; Benjamin J. Dugan; Daming Feng; Diane E. Gingrich; Tao Guo; Koc-Kan Ho; Keith S. Learn; Joseph G. Lisko; Rong-Qiang Liu; Eugen F. Mesaros; Karen L. Milkiewicz; Gregory R. Ott; Jonathan Parrish; Jay Theroff; Tho V. Thieu; Rabindranath Tripathy; Theodore L. Underiner; Jason C. Wagner; Linda Weinberg; Gregory J. Wells; Ming You; Craig A. Zificsak
Archive | 2010
Matthew A. Curry; Bruce D. Dorsey; Benjamin J. Dugan; Diane E. Gingrich; Eugen F. Mesaros; Karen L. Milkiewicz
Archive | 2015
Bruce D. Dorsey; Benjamin J. Dugan; Katherine M Fowler; Robert L. Hudkins; Eugen F. Mesaros; Nathaniel Jt Monck; Emma L. Morris; Ikeoluwa Olowoye; Gregory R. Ott; Gregoire A. Pave; Jonathan R A Roffey; Christelle N. Soudy; Craig A. Zificsak; Allison L. Zulli
Bioorganic & Medicinal Chemistry Letters | 2011
Eugen F. Mesaros; Jason P. Burke; Jonathan Parrish; Benjamin J. Dugan; Andrew V. Anzalone; Thelma S. Angeles; Mark S. Albom; Lisa D. Aimone; Matthew R. Quail; Weihua Wan; Lihui Lu; Zeqi Huang; Mark A. Ator; Bruce Ruggeri; Mangeng Cheng; Gregory R. Ott; Bruce D. Dorsey
Archive | 2017
Allison L. Zulli; Benjamin J. Dugan; Bruce D. Dorsey; Christelle N. Soudy; Craig A. Zificsak; Emma L. Morris; Eugene F Mesaros; Gregorie A Pave; Gregory R. Ott; Henry J. Breslin; Ikeoluwa Olowoye; Jonathan R A Roffey; Katherine M Fowler; Ming Tao; Nathaniel Jt Monck; Robert L. Hudkins
Archive | 2016
Robert L. Hudkins; Gregory R. Ott; Henry J. Breslin; Bruce D. Dorsey; Benjamin J. Dugan; Katherine M Fowler; Eugen F. Mesaros; Nathaniel Jt Monck; Emma L. Morris; Ikeoluwa Olowaye; Gregoire A. Pave; Jonathan R A Roffey; Christelle N. Soudy; Ming Tao; Craig A. Zificsak; Allison L. Zulli
Archive | 2016
Bruce D. Dorsey; Benjamin J. Dugan; Katherine M Fowler; Robert L. Hudkins; Eugen F. Mesaros; Nathaniel Jt Monck; Emma L. Morris; Ikeoluwa Olowoye; Gregory R. Ott; Gregoire A. Pave; Jonathan R A Roffey; Christelle N. Soudy; Craig A. Zificsak