Approaches to discover non-ATP site kinase inhibitorsThis article is part of a MedChemComm 'New Talents' issue highlighting the work of outstanding rising scientists in medicinal chemistry research
The catalytic domain of kinases shows a high degree of sequence homology, especially for kinases that belong to the same family. They share a common ATP binding site with a conserved activation loop and similar three-dimensional structure. Consequently, a major challenge in kinase research exists in...
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| Main Authors | , |
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| Format | Journal Article |
| Language | English |
| Published |
20.12.2012
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| Online Access | Get full text |
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| Summary: | The catalytic domain of kinases shows a high degree of sequence homology, especially for kinases that belong to the same family. They share a common ATP binding site with a conserved activation loop and similar three-dimensional structure. Consequently, a major challenge in kinase research exists in achieving selectivity among the >500 family members, since they all process the same substrate. In addition to requiring selectivity against other kinases, ATP site inhibitors must also bind tightly to overcome the high physiological concentration of ATP in the cell. Furthermore, the development of novel ATP site inhibitors is becoming increasingly challenging, as many ATP competitive scaffolds have previously been disclosed. In order to develop compounds with better selectivity among kinases, inhibitors that bind outside the ATP site show great promise and are currently being explored by many groups. This review will highlight the most commonly used methods to discover small molecule Type III and IV kinase inhibitors.
This review will highlight the most commonly used methods to discover small molecule Type III/IV kinase inhibitors. |
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| Bibliography: | This article is part of a MedChemComm 'New Talents' issue highlighting the work of outstanding rising scientists in medicinal chemistry research. Lori earned her Ph.D. from the University of Pennsylvania in 2001 in Professor Jeffrey Winkler's laboratory. She started her professional career as a medicinal chemist at Wyeth Research (now Pfizer). Over the past 10+ years, her work has spanned various stages of research from early exploratory to late discovery. Lori has led several teams from HTS to lead discovery. She also advanced several late stage programs and as a member of the norepinephrine reuptake inhibitor (NRI) program at Wyeth, Lori designed and synthesized a compound that entered Phase I clinical trials for the treatment of vasomotor symptoms (VMS). She has worked in multiple therapeutic areas, including inflammation, cardiovascular, metabolic diseases, and women's health. At present, Lori is leading the chemistry design efforts as a Principal Research Scientist within Pfizer's Orphan and Genetic Disease Research Unit. Eddine received a Ph.D. from Pierre & Marie Curie University in Paris in 1992 followed by a postdoc at the Mayo Clinic Florida. He has worked at several companies, including DuPont Pharmaceuticals and Wyeth. He joined Pfizer in 2009 through the Wyeth acquisition where he was leading the Med Chem group in Cambridge, MA. He has worked on a range of programs including oncology, cardiovascular, metabolic diseases and inflammation with multiple compounds advancing to the clinic. He has championed the use of fragments on multiple programs. He is currently working in the Orphan and Genetic Disease Research Unit with a focus on understanding and tackling protein misfolding with small molecules. He is co-chair of the Pfizer Medicinal Chemistry Design Network Group. |
| ISSN: | 2040-2503 2040-2511 |
| DOI: | 10.1039/c2md20180a |