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      Therapeutic target database update 2014: a resource for targeted therapeutics

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          Abstract

          Here we describe an update of the Therapeutic Target Database ( http://bidd.nus.edu.sg/group/ttd/ttd.asp) for better serving the bench-to-clinic communities and for enabling more convenient data access, processing and exchange. Extensive efforts from the research, industry, clinical, regulatory and management communities have been collectively directed at the discovery, investigation, application, monitoring and management of targeted therapeutics. Increasing efforts have been directed at the development of stratified and personalized medicines. These efforts may be facilitated by the knowledge of the efficacy targets and biomarkers of targeted therapeutics. Therefore, we added search tools for using the International Classification of Disease ICD-10-CM and ICD-9-CM codes to retrieve the target, biomarker and drug information (currently enabling the search of almost 900 targets, 1800 biomarkers and 6000 drugs related to 900 disease conditions). We added information of almost 1800 biomarkers for 300 disease conditions and 200 drug scaffolds for 700 drugs. We significantly expanded Therapeutic Target Database data contents to cover >2300 targets (388 successful and 461 clinical trial targets), 20 600 drugs (2003 approved and 3147 clinical trial drugs), 20 000 multitarget agents against almost 400 target-pairs and the activity data of 1400 agents against 300 cell lines.

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          Most cited references 47

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          Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.

          Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
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            The properties of known drugs. 1. Molecular frameworks.

            In order to better understand the common features present in drug molecules, we use shape description methods to analyze a database of commercially available drugs and prepare a list of common drug shapes. A useful way of organizing this structural data is to group the atoms of each drug molecule into ring, linker, framework, and side chain atoms. On the basis of the two-dimensional molecular structures (without regard to atom type, hybridization, and bond order), there are 1179 different frameworks among the 5120 compounds analyzed. However, the shapes of half of the drugs in the database are described by the 32 most frequently occurring frameworks. This suggests that the diversity of shapes in the set of known drugs is extremely low. In our second method of analysis, in which atom type, hybridization, and bond order are considered, more diversity is seen; there are 2506 different frameworks among the 5120 compounds in the database, and the most frequently occurring 42 frameworks account for only one-fourth of the drugs. We discuss the possible interpretations of these findings and the way they may be used to guide future drug discovery research.
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              International statistical classification of diseases and related health problems. Tenth revision.

               G Brämer (1987)
              The International Classification of Diseases has, under various names, been for many decades the essential tool for national and international comparability in public health. This statistical tool has been customarily revised every 10 years in order to keep up with the advances of medicine. At first intended primarily for the classification of causes of death, its scope has been progressively widening to include coding and tabulation of causes of morbidity as well as medical record indexing and retrieval. The ability to exchange comparable data from region to region and from country to country, to allow comparison from one population to another and to permit study of diseases over long periods, is one of the strengths of the International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD). WHO has been responsible for the organization, coordination and execution of activities related to ICD since 1948 (Sixth Revision of the ICD) and is now proceeding with the Tenth Revision. For the first time in its history the ICD will be based on an alphanumeric coding scheme and will have to function as a core classification from which a series of modules can be derived, each reaching a different degree of specificity and adapted to a particular specialty or type of user. It is proposed that the chapters on external causes of injury and poisoning, and factors influencing health status and contact with health services, which were supplementary classifications in ICD-9, should form an integral part of ICD-10. The title of ICD has been amended to "International Statistical Classification of Diseases and Related Health Problems"', but the abbreviation "ICD" will be retained.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                January 2014
                20 November 2013
                20 November 2013
                : 42
                : D1 , Database issue
                : D1118-D1123
                Affiliations
                1Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, 117543 Singapore, 2Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China, 3NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117456, Singapore, 4College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s Republic of China, 5State Key Laboratory of Medicinal Chemistry & Biology, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, People’s Republic of China, 6Computation and Systems Biology, Singapore-MIT Alliance, National University of Singapore, Singapore and 7Innovative Drug Research Centre and College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, People’s Republic of China
                Author notes
                *To whom correspondence should be addressed. Tel: +65 6516 6877; Fax: +65 6774 6756; Email: phacyz@ 123456nus.edu.sg
                Correspondence may also be addressed to L. Tao. Tel: +65 9105 6863; Fax: +65 6774 6756; Email: g0901898@ 123456nus.edu.sg

                The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

                Article
                gkt1129
                10.1093/nar/gkt1129
                3964951
                24265219
                © The Author(s) 2013. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 6
                Categories
                VI. Genomic variation, diseases and drugs
                Custom metadata
                1 January 2014

                Genetics

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