Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

Regan, John; Capolino, Alison J.; Cirillo, Pier F.; Gilmore, Thomas D.; Graham, Anne G.; Hickey, Eugene R.; Kroe, Rachel R.; Madwed, Jeffrey; Moriak, Monica; Nelson, Richard M.; Pargellis, Christopher A.; Swinamer, Alan; Torcellini, Carol A.; Tsang, Michele; Moss, Neil

doi:10.1021/jm030121k

Cited by 108 publications

(82 citation statements)

References 32 publications

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“…We observe the standard H bonding between the urea linker of the SKR compounds with CDK8/CycC as reported for DFG-out binders such as BIRB796 (12,13,25,31), but only further H bonding with the hinge region triggers a detectable residence time. This is consistent with literature reporting that solvent-shielded H bonding slows down dissociation (32).…”

Section: Discussionsupporting

confidence: 77%

Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

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

120

136

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In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure-kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket.kinetic profiling | structure-based drug design T he cyclin-dependent kinase 8/cyclin C (CDK8/CycC) complex is a potent oncogene (1-4), involved in transcription and regulation of transcriptional activity (5-10), linked to epigenetic processes (11), and regarded as an attractive drug target. The recent clinical success of the small molecule inhibitors sorafenib (BAY-43006, Bayer Pharma) and imatinib (STI-571, Novartis Pharma AG) has been attributed to their deep pocket binding mode (12). The "deep pocket" (13) is adjacent to the kinase ATP binding site and accessible in protein kinases by the rearrangement of the DFG motif (a short motif composed of the residues AspPhe-Gly near the N-terminal region of the activation loop) from the active (DFG-in) to the inactive state (DFG-out) (13,14). Binding of a type II compound to such a DFG-out conformation often includes slow binding kinetics (15) with a prolonged "residence time," which is defined as the period for which a target is occupied by a compound (16). Residence time is currently considered to be a key success factor for compound optimization during drug discovery and perhaps as important as the apparent affinity such as half-inhibitory concentration (IC 50 ) or dissociation constant (K d ) (16,17). Accordingly, residence time could be a key to providing enhanced potency in vivo (18) and a means to improve the correlation of in vitro and in vivo efficacy of drugs (19). Despite the increased acceptance of the need to understand binding kinetics, the interplay between compound-target interactions and binding kinetics is in general too complex and poorly understood to enable prediction of the essential dynamic properties. The impact of the combination of kinetic data of proteininhibitor interactions with crystallographic studies has been recognized with pioneer studies such as bovine trypsin in complex with the bovine pancreatic trypsin inhibitor (20). The concept of structure-activity relationships describing the interdependency between binding affinity and compound structure has been well explored in the l...

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Section: Discussionsupporting

confidence: 77%

Structure–kinetic relationship study of CDK8/CycC specific compounds

Schneider

Böttcher²,

Huber

et al. 2013

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

120

136

View full text Add to dashboard Cite

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“…18 We investigated MAPK p38 signaling in our model by using a novel p38 MAPK-␣ and -␤ inhibitor (BIRB796). 27 Because transgenic rats die suddenly, we also entertained the possibility of an arrhythmogenic death in the animals and investigated electrical remodeling. …”

mentioning

confidence: 99%

p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II–Induced Target Organ Damage

et al. 2007

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We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.

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“…The procedure entails the reaction of b-ketonitrile 4 with benzylhydrazine (3), followed by ring closure of hydrazone 5 in a mixture of ethanol and hydrochloric acid [22]. The basis of this nitrile 4 process involves reaction of the enolate of acetonitrile with ethyl acetate and an inverse addition of the enolate suspension to an acetic acid solution of benzylhydrazine (3) [21].…”

Section: Resultsmentioning

confidence: 99%