Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation

Gill, Adrian L.; Frederickson, Martyn; Cleasby, Anne; Woodhead, Steven J.; Carr, Maria G.; Woodhead, Andrew J.; Walker, Margaret T; Congreve, Miles; Devine, Lindsay A.; Tisi, Dominic; O’Reilly, Marc; Seavers, Lisa C A; Davis, Deborah; Curry, Jane; Anthony, Rachel; Padova, Alessandro; Murray, Christopher W.; Carr, Robin A. E.; Jhoti, Harren

doi:10.1021/jm049575n

Cited by 188 publications

(171 citation statements)

References 37 publications

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“…Typically, as the potency of a compound increases, parallel gains in selectivity occur (22,23). Regression analysis was used to determine whether the profiling data are consistent with this premise.…”

Section: Generation and Validation Of A Tel-fused Tyrosine Kinase Panmentioning

confidence: 99%

An efficient rapid system for profiling the cellular activities of molecular libraries

Melnick

Janes

Kim

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

168

130

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Rapid quantitative methods for characterizing small molecules, peptides, proteins, or RNAs in a broad array of cellular assays would allow one to discover new biological activities associated with these molecules and also provide a more comprehensive profile of drug candidates early in the drug development process. Here we describe a robotic system, termed the automated compound profiler, capable of both propagating a large number of cell lines in parallel and assaying large collections of molecules simultaneously against a matrix of cellular assays in a highly reproducible manner. To illustrate its utility, we have characterized a set of 1,400 kinase inhibitors in a panel of 35 activated tyrosine-kinasedependent cellular assays in dose-response format in a single experiment. Analysis of the resulting multidimensional dataset revealed subclusters of both inhibitors and kinases with closely correlated activities. The approach also identified activities for the p38 inhibitor BIRB796 and the dual src͞abl inhibitor BMS-354825 and exposed the expected side activities for Glivec͞STI571, including cellular inhibition of c-kit and platelet-derived growth factor receptor. This methodology provides a powerful tool for unraveling the cellular biology and molecular pharmacology of both naturally occurring and synthetic chemical diversity.drug discovery ͉ high-throughput screening ͉ tyrosine kinase T he ability to simultaneously interrogate the activities of a library of molecules against a large panel of cellular assays would provide a rapid efficient means to begin to characterize and correlate the biological properties of both natural and synthetic chemical diversity. For example, libraries of noncoding RNAs, mutant growth factors, small molecule kinase inhibitors, or even existing drugs could be assayed for their potency and selectivity in pathway-based or receptor screens or toxicity and metabolic stability in diverse cell types to discover a new biological activity or optimize the pharmacological properties of a molecule (1-3). Although whole-cell systems represent an attractive milieu to characterize gene and small-molecule function, no robust and systematic method exists to correlate chemical structure and biological activity across a large number of molecules and cellular assays. To address this problem, we have developed an approach that affords rapid cost-effective broad-based cellular profiling in parallel against molecular libraries. An industrial-scale automated compound profiling (ACP) system has been designed, which consists of an automated tissue culture system for propagating cell lines, integrated with a system for automatically performing miniaturized cell-based assays in 384-or 1,536-well microplates. The ACP can rapidly test thousands of arrayed molecules, in replicates, in doseresponse format against hundreds of unique cellular assays in a single experiment.To demonstrate this capability, we focused on the problem of identifying selective small-molecule inhibitors of protein tyrosine kinases. Tyrosine ...

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Section: Generation and Validation Of A Tel-fused Tyrosine Kinase Panmentioning

confidence: 99%

An efficient rapid system for profiling the cellular activities of molecular libraries

Melnick

Janes

Kim

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

168

130

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“…There is an overwhelming evidence indicating that various heterocyclic cores attached to a diaryl system possess diverse pharmacological activities viz., COX II inhibition [4], allosteric modulation of GABA A receptor [5] and estrogen receptor [6], adenosine receptor antagonism [7], selective p38a inhibition [8], cannabinoid receptor antagonism [9], antimitotic activity [10] (combretastatin analogs), antiplatelet activity [11] and anti-HIV-1 activity [12] (TMC-125).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Ramajayam

Giridhar

Yadav

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.

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“…It also confirms that interaction with DFG-in binders is compatible with the DFG-out conformation of the DFG loop, which has already been put to use in combining DFG-in and DFG-out ligands. [23] To date, indirect evidence for a slow DFG-inQDFG-out equilibrium has come from analyses of rates for the binding of different DFG-out inhibitors. While the rates of DFG-in inhibitors binding to the protein can be regarded as diffusion controlled (Table 1), the rates of DFG-out inhibitors of similar molecular size are two orders of magnitude lower.…”

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confidence: 99%

NMR Characterization of Kinase p38 Dynamics in Free and Ligand‐Bound Forms

et al. 2006

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In its apo state kinase p38 effects slow motions that can be detected in the NMR spectrum. One of the affected parts is the pharmacologically interesting DFG motif. Diarylurea inhibitors that bind to the DFG‐out conformation lock this motif in a defined state, whereas DFG‐in inhibitors that bind to the adjacent hinge region leave the flexibility of the DFG motif unaffected (see crystal structure of the complex of p38 with the inhibitor SB203580).

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Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation

Cited by 188 publications

References 37 publications

An efficient rapid system for profiling the cellular activities of molecular libraries

An efficient rapid system for profiling the cellular activities of molecular libraries

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

NMR Characterization of Kinase p38 Dynamics in Free and Ligand‐Bound Forms

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