The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition

Genetic Interaction of Centrosomin and Bazooka in Apical Domain Regulation in Drosophila Photoreceptor

Cell polarity genes including Crumbs (Crb) and Par complexes are essential for controlling photoreceptor morphogenesis. Among the Crb and Par complexes, Bazooka (Baz, Par-3 homolog) acts as a nodal component for other cell polarity proteins. Therefore, finding other genes interacting with Baz will help us to understand the cell polarity genes' role in photoreceptor morphogenesis. mutation on developing eyes to determine its role in photoreceptor morphogenesis. We found that Cnn is dispensable for retinal differentiation in eye imaginal discs during the larval stage. However, photoreceptors deficient in Cnn display dramatic morphogenesis defects including the mislocalization of Crumbs (Crb) and Bazooka (Baz) during mid-stage pupal eye development, suggesting that Cnn is specifically required for photoreceptor morphogenesis during pupal eye development. This role of Cnn in apical domain modulation was further supported by Cnn's gain-of-function phenotype. Cnn overexpression in photoreceptors caused the expansion of the apical Crb membrane domain, Baz and adherens junctions (AJs). photoreceptor

Non Mycobacterial Virulence Genes in the Genome of the Emerging Pathogen Mycobacterium abscessus

Mycobacterium abscessus is an emerging rapidly growing mycobacterium (RGM) causing a pseudotuberculous lung disease to which patients with cystic fibrosis (CF) are particularly susceptible. We report here its complete genome sequence. The genome of M. abscessus (CIP 104536T) consists of a 5,067,172-bp circular chromosome including 4920 predicted coding sequences (CDS), an 81-kb full-length prophage and 5 IS elements, and a 23-kb mercury resistance plasmid almost identical to pMM23 from Mycobacterium marinum. The chromosome encodes many virulence proteins and virulence protein families absent or present in only small numbers in the model RGM species Mycobacterium smegmatis. Many of these proteins are encoded by genes belonging to a “mycobacterial” gene pool (e.g. PE and PPE proteins, MCE and YrbE proteins, lipoprotein LpqH precursors). However, many others (e.g. phospholipase C, MgtC, MsrA, ABC Fe(3+) transporter) appear to have been horizontally acquired from distantly related environmental bacteria with a high G+C content, mostly actinobacteria (e.g. Rhodococcus sp., Streptomyces sp.) and pseudomonads. We also identified several metabolic regions acquired from actinobacteria and pseudomonads (relating to phenazine biosynthesis, homogentisate catabolism, phenylacetic acid degradation, DNA degradation) not present in the M. smegmatis genome. Many of the “non mycobacterial” factors detected in M. abscessus are also present in two of the pathogens most frequently isolated from CF patients, Pseudomonas aeruginosa and Burkholderia cepacia. This study elucidates the genetic basis of the unique pathogenicity of M. abscessus among RGM, and raises the question of similar mechanisms of pathogenicity shared by unrelated organisms in CF patients

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition

The World Saffron and Crocus collection: strategies for establishment, management, characterisation and utilisation

[EN] Since 2007, the European Commission AGRI GEN RES 018 "CROCUSBANK" action has permitted the creation of the alleged World Saffron and Crocus Collection (WSCC), a unique collection which contains a representation of the genetic variability present in saffron crop and wild relatives at global scale. At present the germplasm collection, housed at the Bank of Plant Germplasm of Cuenca (BGV-CU, Spain), consists of 572 preserved accessions representing 47 different Crocus species (including saffron Crocus) and is expected to increase up to more than 600 accessions by the end of CROCUSBANK action (May 2011). The preserved biodiversity of saffron (Crocus sativus L.) covers a wide range of the genetic variability of the crop and currently consists of 220 accessions from 15 countries: 169 of these come from European cultivation countries, 18 from commercial areas in non EU countries, 26 from regions of minimal or relict production and/or from abandoned fields and 7 from commercial nurseries. The non-saffron Crocus collection currently comprises 352 accessions: 179 collected from the wild in 12 countries of natural distribution, 24 from donations of public and private institutions, 91 from commercial nurseries and 58 acquired from BGV-CU collection management. Here we provide a record of collections, activities concerns and current strategies for documentation, conservation, characterisation, and management of the collection as important tools for researchers with interest in these valuable genetic resources.Many of the results presented in this paper are an outcome of the project "Genetic Resources of Saffron and Allies" (CROCUSBANK, http://www.crocusbank.org). This action receives financial support from the European Commission, Directorate General for Agriculture and Rural Development, under the Council Regulation (EC) No. 870/2004 establishing a Community Programme on the conservation, characterisation, collection, and utilisation of genetic resources in Agriculture (018 AGRI GEN RES ACTION). In addition some of the activities presented took a long period of time and have been partially supported by the following projects or actions: RFP-1 (Consejeria de Agricultura, JCCM, Spain), 05-172/IA-35 (Consejeria de Agricultura, JCCM, Spain), PAI09-0021-0413 and PBI09-0025-1537 (Consejeria de Educacion y Ciencia, JCCM, Spain), RF2008-0012-C03 (Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria, MEC, Spain), RF2004-0032-C03 (Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria, MEC, Spain). Special thanks to the following donor's institutions: Regulatory Council for the "La Mancha Saffron" designation of origin (DOP, La Mancha, Spain); The Royal Veterinary and Agricultural University (Denmark); Asociacion de Naturalistas del Sureste (ANSE, Spain); Centro de Investigacion y Tecnologia Agroalimentaria de Aragon (CITA, Spain); MTS Schipper & Elberse (Holland); Botanic Garden Utrecht University (The Netherlands); National Botanic Garden of Belgium (Belgium); Jardin Alpin du Lautaret (France); Frega S. R. L. (Argentina); Conservatoire et Jardin Botaniques de la Ville Geneve (Switzerland); Herbario Sant (Spain); Conservatoire Botanique National de Brest (France); Jardin des Plantes Medicinales et Aromatiques (France); Baby Brand Saffron (India); Azienda Agricola di Di Marco Amalia (Italy); Azienda Agricola IL Vecchio Maneggio (Italy); New Zealand Institute for Crop and Food Research (New Zealand); Ljubljana University Botanic Garden (Slovenia) and the Afghanistan Government. 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