Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase

The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.     

Web-based live telesurgery for minimally invasive procedures in children as an educational tool

Three surgeries--a laparoscopic Nissen fundoplication, a thoracoscopic left lower lobectomy, and a laparoscopically assisted pull-through for imperforate anus--were broadcast live over the internet. Pediatric surgeons and appropriate societies were notified of the broadcasts by e-mail. Viewers registered on-line at no cost. The procedures could be viewed from any computer connected to the internet. There was a surgeon and on-site moderator for each procedure and viewers could ask questions in real time via e-mail. The three surgeries were archived on the web for later viewing. The broadcasts were transmitted without problem. There were over 8500 preliminary hits at the web site, from 49 countries. By report, many sites had multiple viewers. As of April 2006 there have been over 19,000 hits and 5600 viewers have registered to watch the archived video. Web-based broadcasts appear to be an efficient way for sharing surgical experience and may be a way to expand surgeon education in select cases, especially in an era of dispersal of index cases, work hour restrictions, and evolving technologies. A network of pediatric programs linked via the web might provide an important educational tool.     

PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non-small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members.