A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.

A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies.

The impact of a publication in a particular medical area is reflected by the number of times the article is included as a citation. It is not known, however, which articles are cited the most in primary care journals. In our study, we aimed to identify the 100 most cited articles in primary care medicine and analyze their characteristics.We searched the Science Citation Index Expanded for articles published in 18 primary care journals using the subject category “Primary health care.” We identified 100 articles in primary health care that were the most cited. We analyzed the characteristics of these articles using the title, number of citations, citation density, year of publication, journal source, decade published, country of origin, institution, author names, and type of article.The 100 articles that were cited the most were published between the years 1977 and 2009. The 1990s decade was the most productive decade. The number of citations ranged from 117 to 775. The articles were published in 9 journals and the journal with the largest number of most cited articles (n = 33) was the Journal of Family Practice. This was followed by the British Journal of General Practice (n = 17) and the journal Family Practice (n = 16). The United States was the most productive country (n = 59); the United Kingdom was next (n = 25) and this was followed by Canada (n = 5) and The Netherlands (n = 5). The most popular article type was a review article and this was followed by a qualitative study and then methodological study.Our study provides insight into the historical development of primary care studies, based on citations, and provides the foundation for further investigations.