Suchergebnisse

Recent network and system biology analyses suggest that most complex diseases are regulated by robust and highly interconnected pathways that could be better modulated by small molecules binding to multiple biological targets. These pieces of evidence recently led to devote efforts on identifying single chemical entities that bind to two different disease-relevant targets. Here, we first predicted in silico and later confirmed in vitro that UPF 1069, a known bioactive poly(ADP-ribose) polymerase-1/2 (PARP1/2) molecule, and hydroxyfasudil, a known bioactive Rho-associated protein kinase-1/2 (ROCK1/2) molecule, have low-micromolar cross-affinity for ROCK1/2 and PARP1/2, respectively. These molecules can now be regarded as chemical seeds from which pharmacological tools could be generated to study the impact of dual inhibition of PARPs and ROCKs in preclinical models of a variety of complex diseases where both targets are involved. ; This research was funded by the People Program (Marie Curie Actions) of the 7th Framework Program of the European Union (FP7/2007−2013) under REA grant agreement no. 600388 (TECNIOspring program) (A.A.A.); the Agency of Business Competitiveness of the Government of Catalonia ACCIO (A.A.A.); the Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (204735/Z/16/Z) (A.A.A.); and the Spanish Ministerio de Economia y Competitividad grant BIO2014-54404-R (J.M.).

This project was developed under the Innovative Medicines Initiative Joint Undertaking Open PHACTS Project, Grant Agreement Number 115191, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and members of the European Federation of Pharmaceutical Industries and Associations (EFPIA)

Large efforts dedicated to detect somatic alterations across tumor genomes/exomes are expected to produce significant improvements in precision cancer medicine. However, high inter-tumor heterogeneity is a major obstacle to developing and applying therapeutic targeted agents to treat most cancer patients. Here, we offer a comprehensive assessment of the scope of targeted therapeutic agents in a large pan-cancer cohort. We developed an in silico prescription strategy based on identification of the driver alterations in each tumor and their druggability options. Although relatively few tumors are tractable by approved agents following clinical guidelines (5.9%), up to 40.2% could benefit from different repurposing options, and up to 73.3% considering treatments currently under clinical investigation. We also identified 80 therapeutically targetable cancer genes. ; We acknowledge funding from the Spanish Ministry of Economy and Competitiveness (grant number SAF2012-36199), La Fundació la Marató de TV3, and the Spanish National Institute of Bioinformatics (INB). C.R.-P. and M.P.S. are supported by an FPI fellowship. D.T. is supported by the People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union (FP7/2007-2013) under REA grant agreement number 600388 and by the Agency of Competitiveness for Companies of the Government of Catalonia, ACCIÓ. A.G.-P. is supported by a Ramón y Cajal contract.