- Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
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The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.
- Getlik, Matth?us,Grütter, Christian,Simard, Jeffrey R.,Klüter, Sabine,Rabiller, Matthias,Rode, Haridas B.,Robubi, Armin,Rauh, Daniel
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Read Online
- Synthesis, characterization and antiinflammatory activity of novel pyrazolyl ketoamides
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Compounds containing pyrazolylurea group are known to possess potent anti-inflammatory activity by inhibiting cell signalling system. One of the potent compounds has demonstrated CNS related adverse effects in human studies which has further intensified the quest to search potent but safe antiinflammatory agents. In the present study, an attempt has been made to modify the urea group into α-ketoamide group. The synthesis involved the coupling of 5-aminopyrazole with substituted α-keto acids in presence of a coupling agent to afford the desired compounds and the structures of the synthesized compounds have been confirmed by spectral data. Compounds have been screened for antiinflammatory activity by carrageenan induced rat paw method. Compounds 6c, 6e and 6f demonstrate greater than 70% paw oedema protection when compared with indomethacin. The preliminary structure activity relationship suggests that the electron withdrawing groups are essential for potent antiinflammatory activity of compounds.
- Mahaveer,Kulkarni,Radakrishna,Chandrashekar,Achaiah
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p. 818 - 823
(2013/07/26)
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- Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors
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Kinase disregulation disrupts the intricate network of intracellular signaling pathways and contributes to the onset of diseases such as cancer. Although several kinase inhibitors are on the market, inhibitor selectivity and drug resistance mutations persist as fundamental challenges in the development of effective long-term treatments. Chemical entities binding to less conserved allosteric sites would be expected to offer new opportunities for scaffold development. Because no high-throughput method was previously available, we developed a fluorescence-based kinase binding assay for identifying and characterizing ligands which stabilize the inactive kinase conformation. Here, we present a description of the development and validation of this assay using the serine/threonine kinase p38R. By covalently attaching fluorophores to the activation loop of the kinase, we were able to detect conformational changes and measure the Kd, kon, and koff associated with the binding and dissociation of ligands to the allosteric pocket. We report the SAR of a synthesized focused library of pyrazolourea derivatives, a scaffold known to bind with high affinity to the allosteric pocket of p38R. Additionally, we used protein X-ray crystallography together with our assay to examine the binding and dissociation kinetics to characterize potent quinazoline- and quinoline-based type II inhibitors, which also utilize this binding pocket in p38α. Last, we identified the b-Raf inhibitor sorafenib as a potent low nanomolar inhibitor of p38α and used protein X-ray crystallography to confirm a unique binding mode to the inactive kinase conformation.
- Simard, Jeffrey R.,Getlik, Matthaeus,Gruetter, Christian,Pawar, Vijaykumar,Wulfert, Sabine,Rabiller, Matthias,Rauh, Daniel
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supporting information; experimental part
p. 13286 - 13296
(2010/01/30)
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- 1-Phenyl-5-pyrazolyl ureas: Potent and selective p38 kinase inhibitors
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Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM). (C) 2000 Elsevier Science Ltd.
- Dumas, Jacques,Hatoum-Mokdad, Holia,Sibley, Robert,Riedl, Bernd,Scott, William J.,Monahan, Mary Katherine,Lowinger, Timothy B.,Brennan, Catherine,Natero, Reina,Turner, Tiffany,Johnson, Jeffrey S.,Schoenleber, Robert,Bhargava, Ajay,Wilhelm, Scott M.,Housley, Timothy J.,Ranges, Gerald E.,Shrikhande, Alka
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p. 2051 - 2054
(2007/10/03)
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