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Dive into the research topics where Joseph G. Naglich is active.

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Featured researches published by Joseph G. Naglich.


Archive | 2003

Cancer Drug Discovery and Development

Jeffrey S. Humphrey; Karen Price; Elora Gupta; Andrew Douglas Baxter; John Bird; Daryl Sonnichsen; Joseph G. Naglich

A significant amount of clinical research has been conducted with small molecules that inhibit matrix metalloproteinases (MMP), metal-containing enzymes that degrade the extracellular matrix and are implicated in tumor progression and angiogenesis (1–3). The majority of matrix metalloproteinase inhibitors (MMPIs) are designed with a concept similar to protease inhibitors used in the treatment of acquired immunodeficiency syndrome. MMPIs are currently under development for the treatment of a variety of diseases most notably cancer (3). Unlike conventional chemotherapy or radiation therapy, MMPIs are expected to slow tumor growth and prolong survival without causing detectable shrinkage of tumors. Because MMPIs are predicted to slow tumor growth but not shrink tumors, clinical development is not guided purely by objective tumor responses; proving the therapeutic value of these molecules will therefore require randomized placebo-controlled trials with assessment of the impact of drug treatment compared to placebo. Proof that these compounds are effective cytostatic agents will require demonstrating a survival advantage when compared to a placebo in a randomized, controlled trial.


Journal of Medicinal Chemistry | 2015

The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity.

Benjamin A. Seigal; William H. Connors; Andrew Fraley; Robert M. Borzilleri; Percy H. Carter; Stuart Emanuel; Joseph Fargnoli; Kyoung S. Kim; Ming Lei; Joseph G. Naglich; Matthew E. Pokross; Shana Posy; Henry Shen; Neha Surti; Randy Talbott; Yong Zhang; Nicholas K. Terrett

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.


Bioorganic & Medicinal Chemistry Letters | 2012

Identification of a Phenylacylsulfonamide Series of Dual Bcl-2/Bcl-Xl Antagonists.

Heidi L. Perez; Patrizia Banfi; Jay Aaron Bertrand; Zhen Wei Cai; James W. Grebinski; Kyoung S. Kim; Jonathan Lippy; Michele Modugno; Joseph G. Naglich; Robert J. Schmidt; Andrew J. Tebben; Paola Vianello; Donna D. Wei; Liping Zhang; Arturo Galvani; Louis J. Lombardo; Robert M. Borzilleri

A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity.


Bioorganic & Medicinal Chemistry Letters | 2012

Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.

Gretchen M. Schroeder; Donna D. Wei; Patrizia Banfi; Zhen-Wei Cai; Jonathan Lippy; Maria Menichincheri; Michele Modugno; Joseph G. Naglich; Becky Penhallow; Heidi L. Perez; John S. Sack; Robert J. Schmidt; Andrew J. Tebben; Chunhong Yan; Liping Zhang; Arturo Galvani; Louis J. Lombardo; Robert M. Borzilleri

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.


ACS Medicinal Chemistry Letters | 2015

Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer

Yong Zhang; Benjamin A. Seigal; Nicholas K. Terrett; Randy Talbott; Joseph Fargnoli; Joseph G. Naglich; Charu Chaudhry; Shana Posy; Ragini Vuppugalla; Georgia Cornelius; Ming Lei; Chunlei Wang; Yingru Zhang; Robert J. Schmidt; Donna D. Wei; Michael M. Miller; Martin Patrick Allen; Ling Li; Percy H. Carter; Gregory D. Vite; Robert M. Borzilleri

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.


Journal of Medicinal Chemistry | 2015

Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity.

Heidi L. Perez; Charu Chaudhry; Stuart Emanuel; Caroline Fanslau; Joseph Fargnoli; Jinping Gan; Kyoung S. Kim; Ming Lei; Joseph G. Naglich; Sarah C. Traeger; Ragini Vuppugalla; Donna D. Wei; Gregory D. Vite; Randy Talbott; Robert M. Borzilleri

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.


Journal of Biomolecular Screening | 2016

Development of a Human Whole Blood Screening Platform to Monitor JAK/STAT Signaling Using High-Throughput Flow Cytometry

Mark P. Fereshteh; Xin Li; Sha Li; Yi Fan; Rosemary Zhang; Glen A. Farr; Garrett Kolodin; Jonathan Lippy; Joseph G. Naglich; Gary L. Schieven; Liang Schweizer; Litao Zhang

Oral agents targeting Janus-associated kinases (JAKs) are promising new agents in clinical development. To better understand the relationship between JAK inhibition and biological outcome, compounds targeting JAKs were evaluated in peripheral human whole blood. To date, these analyses are low throughput and costly. Here, we developed a robust 384-well, high-throughput flow-based assay approach to screen small molecules for JAK/STAT signaling inhibition in human whole blood. This assay platform provides a highly sensitive analysis of signaling events in blood and facilitates measurement of target engagement. Further, the automation technologies and process optimizations developed here overcame sample integrity, handling, and multiparametric data analysis bottlenecks without affecting assay performance. Together these efforts dramatically increased sample throughput compared to conventional manual flow cytometric approaches and enabled development of novel JAK/STAT inhibitors.


Experimental Cell Research | 2015

Pharmacology of smac mimetics; chemotype differentiation based on physical association with caspase regulators and cellular transport

Randy Talbott; Robert M. Borzilleri; Charu Chaudhry; Joseph Fargnoli; Henry Shen; Craig R. Fairchild; Bryan C. Barnhart; Marie Ortega; Thomas McDonagh; Ragini Vuppugalla; Gregory D. Vite; John T. Hunt; Marco M. Gottardis; Joseph G. Naglich

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Cancer Research | 2001

Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291.

Joseph G. Naglich; Maria Jure-Kunkel; Elora Gupta; Joseph Fargnoli; Arris J. Henderson; Anne Lewin; Randy Talbott; Andy Baxter; John Bird; Ranjev Savopoulos; Ruth Wills; Robert Kramer; Pamela A. Trail


Bioorganic & Medicinal Chemistry Letters | 2006

Inhibitors of human mitotic kinesin Eg5: Characterization of the 4-phenyl-tetrahydroisoquinoline lead series

Christine M. Tarby; Robert F. Kaltenbach; Tram Huynh; Andrew T. Pudzianowski; Henry Shen; Marie Ortega-Nanos; Steven Sheriff; John A. Newitt; Patricia A. McDonnell; Neil T. Burford; Craig R. Fairchild; Wayne Vaccaro; Zhong Chen; Robert M. Borzilleri; Joseph G. Naglich; Louis J. Lombardo; Marco M. Gottardis; George L. Trainor; Deborah L. Roussell

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