Journal ArticleDOI
Rational design of inhibitors that bind to inactive kinase conformations
Yi Liu,Nathanael S. Gray +1 more
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TLDR
A structural analysis of binding modes of known human type II inhibitors are presented and it is demonstrated that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.Abstract:
The majority of kinase inhibitors that have been developed so far—known as type I inhibitors—target the ATP binding site of the kinase in its active conformation, in which the activation loop is phosphorylated. Recently, crystal structures of inhibitors such as imatinib (STI571), BIRB796 and sorafenib (BAY43-9006)—known as type II inhibitors—have revealed a new binding mode that exploits an additional binding site immediately adjacent to the region occupied by ATP. This pocket is made accessible by an activation-loop rearrangement that is characteristic of kinases in an inactive conformation. Here, we present a structural analysis of binding modes of known human type II inhibitors and demonstrate that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.read more
Citations
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Targeting cancer with small molecule kinase inhibitors
TL;DR: This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors, and discusses the current challenges in the field.
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Comprehensive analysis of kinase inhibitor selectivity.
Mindy I. Davis,Jeremy P Hunt,Jeremy P Hunt,Sanna Herrgard,Pietro Ciceri,Pietro Ciceri,Lisa M Wodicka,Lisa M Wodicka,Gabriel Pallares,Gabriel Pallares,Michael D. Hocker,Daniel K Treiber,Daniel K Treiber,Patrick P Zarrinkar,Patrick P Zarrinkar +14 more
TL;DR: Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily.
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Paul Ehrlich's magic bullet concept: 100 years of progress.
Klaus Strebhardt,Axel Ullrich +1 more
TL;DR: The intellectual foundations of the development of cancer drug development are revisited, as many have shown great clinical success and are therefore appropriate to revisit.
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Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
Scott Wilhelm,Jacques Dumas,Lila Adnane,Mark Lynch,Christopher A. Carter,Gunnar Schütz,Karl-Heinz Thierauch,Dieter Zopf +7 more
TL;DR: Data demonstrate that regorafenib is a well‐tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
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Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors
Marcus Bantscheff,Dirk Eberhard,Yann Abraham,Sonja Bastuck,Markus Boesche,Scott Hobson,Toby Mathieson,Jessica Perrin,Manfred Raida,Christina Rau,Valerie Reader,Gavain Sweetman,Andreas Bauer,Tewis Bouwmeester,Carsten Hopf,Ulrich Kruse,Gitte Neubauer,Nigel Ramsden,Jens Rick,Bernhard Kuster,Gerard Drewes +20 more
TL;DR: Quantitative profiling of the drugs Imatinib, dasatinib and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib.
References
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The Protein Kinase Complement of the Human Genome
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
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Protein kinases--the major drug targets of the twenty-first century?
TL;DR: A personal view of some of the most important advances that have shaped this field of protein kinases, after G-protein-coupled receptors.
Journal ArticleDOI
A small molecule-kinase interaction map for clinical kinase inhibitors.
Miles A. Fabian,William H. Biggs,Daniel K. Treiber,Corey E. Atteridge,Mihai Azimioara,Mihai Azimioara,Michael G. Benedetti,Michael G. Benedetti,Todd A. Carter,Pietro Ciceri,Philip T. Edeen,Mark Floyd,Julia M. Ford,Margaret Galvin,Jay L Gerlach,Jay L Gerlach,Robert M. Grotzfeld,Sanna Herrgard,Darren E. Insko,Michael A Insko,Andiliy G. Lai,Jean-Michel Lélias,Shamal A. Mehta,Zdravko V. Milanov,Anne Marie Velasco,Lisa M. Wodicka,Hitesh K. Patel,Patrick P. Zarrinkar,David J. Lockhart +28 more
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Structural mechanism for STI-571 inhibition of abelson tyrosine kinase
Thomas Schindler,William Bornmann,Patricia Pellicena,W. Todd Miller,Bayard D. Clarkson,John Kuriyan +5 more
TL;DR: The results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
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