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Dive into the research topics where Adrian L. Smith is active.

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Featured researches published by Adrian L. Smith.


Methods in Enzymology | 2003

Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions

Christopher Hulme; Hugues Bienayme; Thomas Nixey; Balan Chenera; Wyeth Jones; Paul Tempest; Adrian L. Smith

Publisher Summary This chapter focuses on a particular branch of multicomponent condensation reaction (MCR) methodologies— namely, the postcondensation modifications (or secondary reactions) of isocyanide-based multicomponent reactions (IMCRs). One attractive feature of the multicomponent reaction is the relative ease of its automation. Discrete reactions may be run in parallel by either solution- or solid-phase protocols in a standard 96-well format. One of the methodologies discussed in the chapter is the UDC (Ugi/De-Boc/Cyclize) methodology. The biological utility of 1,4-benzodiazepine-2,5-diones (BDPs) appears in many areas, including the applications as antagonists of the platelet glycoprotein IIb-IIIa, anticonvulsant agents, antihypnotic agents, reverse transcriptase inhibitors, and selective cholecystokinin (CCK) receptor subtype A or B antagonists. The chapter presents three miscellaneous postcondensation modification reactions: (1) TMSN 3 modified Ugi Reactions, (2) postcondensation Passerini reactions, and (3) TMSN 3 -modified Passerini reaction. The TMSN 3 -modified Ugi reaction involves the condensation of an appropriately substituted aldehyde or ketone with a primary or secondary amine.


Cancer Research | 2010

Abstract 21: Selective and potent inhibitors of the mutant B-Raf pathway paradoxically stimulate the MAPK pathway in wild-type B-Raf cells

Josette Carnahan; Pedro J. Beltran; Carol Babij; Quynh Le; Mark J. Rose; Steven Vonderfecht; Joseph L. Kim; Adrian L. Smith; Martin A. Broome; Manory Fernando; Hue Kha; Brian Belmontes; Robert Radinsky; Richard Kendall; Teresa L. Burgess

B-Raf is a member of the Raf family of serine/threonine kinases, which also include A-Raf and C-Raf. While all 3 Raf kinases stimulate the MAPK signaling cascade, B-Raf is the most catalytically active. B-Raf hyperactivity through mutation or over-expression is reported in many solid and hematologic malignancies. An especially high frequency (60%) of activating B-Raf mutations is found in melanoma, with the kinase domain mutant (V600E) accounting for greater than 95% of these. The identification and development of B-Raf inhibitors that selectively block signaling of the V600E B-Raf dependent MAPK pathway may have therapeutic value in these and other malignancies driven by activation of B-Raf. We report here on the characterization of novel, potent and selective small molecule Raf kinase inhibitors demonstrating potent cellular activity. Compound 1 (Smith, DeMorin et al. 2009) exhibits excellent potency in cells harboring V600E B-Raf (P-ERK IC 50 ranging from 1-14nM) however, cells that contain wild type B-Raf are significantly less sensitive to inhibition of MAPK signaling by compound 1 (P-ERK IC 50 ranging from 260nM to > 1μM). This shift in potency between V600E B-Raf versus wt B-Raf cell lines is also observed with cellular viability. In contrast to cells harboring B-Raf mutation, exposure to selected Raf inhibitors resulted in a dose-dependent, and sustained activation of MAPK signaling, increased Raf basal kinase activity and heterodimer stabilization in all wild type B-Raf cell lines examined . In the mutant KRAS MIA PaCa-2 and A549, Raf inhibition by selected compounds led to entry into the cell cycle, 80% increased proliferation, 40% increased colony formation and significantly stimulated tumor growth in vivo (Beltran et al, AACR 2010). Inhibition with structurally distinct Raf inhibitors or isoform specific siRNA knock-down of Raf demonstrated that these effects were mediated directly through Raf. Either A-Raf or C-Raf, mediated the Raf-inhibitor-induced MAPK pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in both malignant and normal cells such as HUVEC cells. Indeed mouse treatment with any of the efficacious inhibitors resulted in hyperplasia observed in the epithelial layer of mouse esophagus and stomach. These data suggest that mutant versus wild type B-Raf MAPK pathways are distinctly regulated in cells. An implication of these results is that certain Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Smith, A. L., F. F. DeMorin, et al. (2009). “Selective Inhibitors of the Mutant B-Raf Pathway: Discovery of a Potent and Orally Bioavailable Aminoisoquinoline.” Journal of Medicinal Chemistry 52(20): 6189-6192. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 21.


Cancer Research | 2010

Abstract 2519: Efficacy of a potent and selective Raf inhibitor against human xenograft models displaying specific genetic mutations in the MAPK signaling pathway

Pedro J. Beltran; Josette Carnahan; Quynh Le; Manory Fernando; Mark J. Rose; Karthik Nagapudi; Adrian L. Smith; Joseph L. Kim; Brian Belmontes; Teresa L. Burgess; Richard Kendall; Robert Radinsky

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: A significant percentage of human melanomas as well as colon, ovarian and thyroid carcinomas display missense mutations in B-Raf which can drive cellular transformation through constitutive activation of the MAPK signaling pathway. Thus, mutant B-Raf represents an attractive target to develop new oncology therapeutics. Here we describe the in vivo potency and efficacy of a novel Raf inhibitor (cmpd 1) against xenograft models displaying mutations in the MAPK signaling pathway. Methods: Established human xenograft models implanted in athymic female nude mice were used to examine the effects of cmpd 1 on P-ERK basal level and tumor growth. For examination of pharmacodynamic effect, cmpd 1 was dosed orally, once for 6-8 hours prior to collection of the xenograft and peripheral blood. Collected xenografts were lysed and levels of P-ERK analyzed by Meso Scale Detection Assay (MSD). Plasma concentrations of cmpd 1 were determined using Quantitative Liquid Chromatography-Tandem Mass Spectometry (LC-MS/MS). In order to study the effects of cmpd 1 on tumor growth inhibition (TGI), mice with established xenografts (∼ 200-250 cubic mm) were randomized into 4 groups (n=10) on day 0. Mice were dosed orally, once (QD) or twice (BID) per day starting on day 1 until completion of the experiment. Tumor volume and body weight were measured twice per week. Significant TGI was determined using repeated measures ANOVA (RMANOVA) followed by the Dunnetts test. Results: Models expressing B-Raf activating mutations (A375, WM-266 and Colo-205) showed significant decreased expression of P-ERK (>70%) and significant TGI, including complete stasis (100% TGI) and regression at 5 mg/kg QD (ED50 1-3 mg/kg). Models with activating NRAS mutations also showed sensitivity to cmpd 1 but higher doses were required to achieve significant reduction of P-ERK level and tumor growth inhibition (ED50 11 mg/kg). Models with activating KRAS mutations displayed responses ranging from stimulation of tumor growth (MiaPaCa-2) to lack of effect (A549) or 40% TGI (HCT-116). These suboptimal responses in KRAS mutant models were observed even when cmpd 1 was dosed at 10 mg/kg BID. Finally, BxPC-3, a xenograft model with a wild-type (WT) MAPK signaling pathway, displayed sensitivity to cmpd 1 albeit to a lesser extend than observed in B-Raf mutant models (ED50 6.0 mg/kg). In most models, TGI was directly correlated to the ability of cmpd 1 to reduce P-ERK levels in vivo. Plasma exposures of cmpd 1 were approximately proportional to the administered dose. Conclusion: These results show that inhibition of P-ERK by this Raf inhibitor can result in significant TGI in mutant B-Raf, NRAS and WT models while significant sensitivity can be lost in KRAS mutant models. In addition, the data also show that under certain circumstances, the inhibition of Raf in KRAS mutant cell lines can result in stimulation of tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2519.


Archive | 2005

Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors

Vinod F. Patel; Joseph L. Kim; Stephanie Geuns-Meyer; Stuart C. Chaffee; Victor J. Cee; Brian L. Hodous; Steven Bellon; Jean-Christophe Harmange; Philip R. Olivieri; Maya C. Thaman; Erin F. DiMauro; John L. Buchanan; David C. Mcgowan; Brian K. Albrecht; Holly L. Deak; Jean E. Bemis; Ryan White; Matthew W. Martin; Gregory J. Habgood; Paul Tempest; Craig E. Masse; William H. Buckner; Bradley J. Herberich; Russell Graceffa; Dawei Zhang; Shimin Xu; Kelvin Sham; Robert M. Rzasa; James Richard Falsey; Partha P. Chakrabarti


Archive | 2008

Pi3 kinase modulators and methods of use

Shon Booker; Noel D'angelo; Derin C. D'amico; Tae-Seong Kim; Longbin Liu; Kristin L. Meagher; Mark H. Norman; Kathleen Panter; Laurie B. Schenkel; Adrian L. Smith; Nuria A. Tamayo; Douglas A. Whittington; Ning Xi; Kevin Yang


Archive | 2006

Nitrogen- containing bicyclic hetroaryl compounds for the treatment of raf protein kinase-mediated diseases

Morin Frenel F. De; Jian J. Chen; Elizabeth M. Doherty; Stephen A. Hitchcock; Qi Huang; Joseph L. Kim; Gang Liu; Thomas Nixey; Nick A. Paras; Jeffrey Petkus; Daniel Martin Retz; Adrian L. Smith; Andrew Tasker; Jiawang Zhu


Archive | 2005

Aminopyrimidine compounds and methods of use

Adrian L. Smith; Paul Edward Brennan; Frenel DeMorin; Gang Liu; Nick A. Paras; Daniel Martin Retz; Elizabeth Rainbeau


Archive | 2010

Inhibitors of PI3 kinase and/or mTOR

Kristin L. Andrews; Yunxin Y. Bo; Shon Booker; Victor J. Cee; Noel D'angelo; Bradley J. Herberich; Fang-Tsao Hong; Claire L.M. Jackson; Brian A. Lanman; Hongyu Liao; Longbin Liu; Nobuko Nishimura; Mark H. Norman; Liping H. Pettus; Anthony B. Reed; Adrian L. Smith; Seifu Tadesse; Nuria A. Tamayo; Bin Wu; Ryan Wurz; Kevin Chao Yang


Archive | 2006

Nitrogen-containing bicyclic heteroaryl compounds and methods of use

Frenel F. De Morin; Jian J. Chen; Elizabeth M. Doherty; Stephen A. Hitchcock; Qi Huang; Joseph L. Kim; Gang Liu; Thomas Nixey; Nick A. Paras; Jeffrey Petkus; Daniel Martin Retz; Adrian L. Smith; Andrew Tasker; Jiawang Zhu


Archive | 2014

Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

Ana Elena Minatti; Jonathan D. Low; Jennifer R. Allen; Albert Amegadzie; James Brown; Michael J. Frohn; Angel Guzman-Perez; Paul E. Harrington; Patricia Lopez; Vu Van Ma; Nobuko Nishimura; Wenyuan Qian; Shannon Rumfelt; Robert M. Rzasa; Kelvin Sham; Adrian L. Smith; Ryan White; Qiufen Xue

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