Caracterisation chez une Annelide Polychete (Nereis diversicolor O. F. Mueller) de peptides apparentes au FMRF-amide. Localisation immunocytochimique - Purification - Structure

SIGLEINIST T 74022 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Le criblage à Roscoff

Les scientifiques de la station biologique de Roscoff (SBR) travaillent depuis plusieurs dizaines d’années sur la régulation de la division cellulaire en utilisant, comme modèles, des organismes marins. Ceci a notamment conduit à l’étude de kinases dépendantes des cyclines (CDK) qui contrôlent le déroulement du cycle cellulaire. Ces cibles ont ensuite été utilisées afin de caractériser des inhibiteurs pharmacologiques, ou « touches » (hits), en mettant en place un criblage automatisé. Le mécanisme d’action des meilleures touches sélectionnées a également été étudié en les dérivant, afin de procéder à des approches de criblages inverses par chromatographie d’affinité. À l’interface entre biologie et chimie, le travail de cette plate-forme place au centre des recherches le composé chimique, qui est à la fois (1) une molécule d’intérêt thérapeutique et (2) un outil moléculaire permettant d’analyser la fonction cellulaire des kinases ciblées. À partir d’organismes marins, huit familles structurales d’inhibiteurs ont été caractérisées sur la plate-forme, et l’espoir est grand de voir la mer nous en apporter de nouveaux, encore plus puissants

Isolation and characterization of authentic Phe-Met-Arg-Phe-NH2 and the novel Phe-Thr-Arg-Phe-NH2 peptide from Nereis diversicolor

International audienc

Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin

Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription and neuronal functions. They are important targets for the design of drugs with anti-mitotic and/or anti-neurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding. The 4-keto group and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hinge region between the N-terminal and C-terminal kinase domain, as has been observed for many CDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitors such as quercetine and flavopiridol showed a different binding mode with the inhibitor rotated by about 180. The structural information of the CDK6-fisetin complex is correlated with the binding affinities of different flavone inhibitors for CDK6. This complex structure is the first description of an inhibitor complex with a kinase from the CDK4/6 subfamily and can provide a basis for selecting and designing inhibitor compounds with higher affinity and specificity

Synthesis and kinase inhibitory potencies of new pyrido[3,4-g]quinazolines substituted at the 8-position

International audienceAs part of the structure-activity relationship study undertaken around the pyrido[3,4-g]quinazoline moiety, new derivatives substituted at the 8-position were synthesized and evaluated regarding their ability to inhibit various protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3). Most active compound exhibited a nanomolar potency toward CLK1, demonstrating that substitution at 8-position is compatible with CLK1 inhibition

Bioactive Metabolites from the Deep Subseafloor Fungus Oidiodendron griseum UBOCC-A-114129

International audienceFour bioactive compounds have been isolated from the fungus UBOCC-A-114129 cultivated from deep subsurface sediment. They were structurally characterized using a combination of LC-MS/MS and NMR analyses as fuscin and its derivatives (dihydrofuscin, dihydrosecofuscin, and secofuscin) and identified as polyketides. Albeit those compounds were already obtained from terrestrial fungi, this is the first report of their production by an species and by the deepest subseafloor isolate ever studied for biological activities. We report a weak antibacterial activity of dihydrosecofuscin and secofuscin mainly directed against Gram-positive bacteria (Minimum Inhibitory Concentration (MIC) equal to Minimum Bactericidal Concentration (MBC), in the range of 100 μg/mL). The activity on various protein kinases was also analyzed and revealed a significant inhibition of CDC2-like kinase-1 (CLK1) by dihysecofuscin

Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies

International audienc

Synthesis and biological evaluation of Haspin inhibitors: kinase inhibitory potency and cellular activity

International audienceHaspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analogue 2a in complex with Haspin using X-ray crystallography

Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2- a ]pyridines derivatives as protein kinase inhibitors

International audienceWe report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC$_{50}$ of 0.7 $\mu$M) and DYRK1A (IC$_{50}$ of 2.6 $\mu$M)

Regorafenib analogues and their ferrocenic counterparts: synthesis and biological evaluation

International audienceApproved by the FDA in 2012, regorafenib is one of the last chance treatments for colorectal cancer. While various analogues have already been prepared, ferrocenic derivatives have never been evaluated. In this study, we prepared various ferrocene-containing derivatives of regorafenib and recorded their biological activity in kinase and cellular assays. This led to the identification of a squaramide derivative which shows a good cellular activity and three ferrocene analogues with promising activity in both kinase and cellular assays