To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a high-content screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to -1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.

01 Jan 2007·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

In Vitro Drug Sensitivity-Gene Expression Correlations Involve a Tissue of Origin Dependency

Q2 · CHEMISTRY

Article

Author: Rickardson, L. ; Larsson, R. ; Andersson, C. R. ; Gustafsson, M. G. ; Isaksson, A. ; Fryknäs, M.

A major concern of chemogenomics is to associate drug activity with biological variables. Several reports have clustered cell line drug activity profiles as well as drug activity-gene expression correlation profiles and noted that the resulting groupings differ but still reflect mechanism of action. The present paper shows that these discrepancies can be viewed as a weighting of drug-drug distances, the weights depending on which cell lines the two drugs differ in.

01 Jan 2007·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

QSAR study of anticoccidial activity for diverse chemical compounds: Prediction and experimental assay of trans-2-(2-nitrovinyl)furan

Q3 · MEDICINE

Article

Author: Yenny González-Díaz ; Nilo Castañedo ; Eugenio Uriarte ; Humberto González-Díaz ; Lourdes Santana ; Ervelio Olazábal

In this work we report a QSAR model that discriminates between chemically heterogeneous classes of anticoccidial and non-anticoccidial compounds. For this purpose we used the Markovian Chemicals in silico Design (MARCH-INSIDE) approach J. Mol. Mod.2002, 8, 237-245; J. Mol. Mod.2003, 9, 395-407]. Linear discriminant analysis allowed us to fit the discriminant function. This function correctly classifies 86.67% of anticoccidial compounds and 96.23% of inactive compounds in the training series. Overall classification is 94.12%. We validated the model by means of an external predicting series, with 86.96% of global predictability. Remarkably, the present model is based on topological as well as configuration-dependent molecular descriptors. Therefore, the model performs timely calculations and allows discrimination between Z/E and chiral isomers. Finally, to exemplify the use of the model in practice we report the prediction and experimental assay of trans-2-(2-nitrovinyl)furan. It is notable that lesion control was 72.86% at mg/kg of body weight with respect to 60% at 125 mg/kg for amprolium (control drug). The back-projection map for this compound predicts a high level of importance for the double bond and for the nitro group in the trans position. We conclude that the MARCH-INSIDE approach enables the accurate fast track identification of anticoccidial hits. Moreover, trans-2-(2-nitrovinyl)furan seems to be a promising drug for the treatment of coccidiosis.

100 Deals associated with Spirogermanium hydrochloride

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Phase 2	United States	Unimed Pharmaceuticals LLC	-
Neoplasms	Phase 2	United States	Unimed Pharmaceutical, Inc.	-
Rheumatic Diseases	Phase 2	-	AbbVie, Inc.	-
Rheumatic Diseases	Phase 2	United States	Unimed Pharmaceutical, Inc.	-

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