Structure Based Design (United States)

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Huanglongbing is the most devastating disease of citrus caused by Candidatus Liberibacter asiaticus (Las). In the present study, we report the discovery of novel small molecule inhibitors against SecA ATPase of Las by using structure based design methods. We built the homology model of SecA protein structure of Las based on the SecA of Escherichia coli. The model was used for in-silico screening of commercially available compounds from ZINC database. Using the glide flexible molecular docking method, twenty structures were chosen for in vitro studies. Five compounds were found to inhibit the ATPase activity of SecA of Las at nano molar concentrations and showed antimicrobial activities against Agrobacterium tumefaciens with MBC ranging from 128 to 256 μg/mL. These compounds appear to be suitable as lead compounds for further development of antimicrobial compounds against Las.

During U.S. Navy undersea acoustic telemetry and ranging (telesonar) engineering tests, probe signals in the 8- to 16-kHz octave will be observed at various ranges and at various locales. Doppler spread and multipath spread will be measured for these waveforms as a function of time. In addition, simultaneous transmission of tonals will allow measurement of the correlation between fades at different frequencies, and hence the coherence bandwidth. Finally, ambient noise will be analyzed for insight into noise statistics and noise nonstationarity. The above information supports signal and receiver design by providing measured, as opposed to theoretical, channel characteristics. These data will also broaden the understanding of geographic and seasonal variabilty of undersea shallow-water channels. This paper describes procedures for extracting these channel statistics from recorded telesonar data. [Work supported by ONR-321.]

Earthquake Engineering & Structural DynamicsVolume 22, Issue 6 p. 547-547 Short Communication Discussion on a paper by Stavros A. Anagnostopoulos and Konstantinos V. Spiliopoulos Bruce F. Maison, Bruce F. Maison SSD Engineering Consultants, Berkeley, California, U.S.A.Search for more papers by this author Bruce F. Maison, Bruce F. Maison SSD Engineering Consultants, Berkeley, California, U.S.A.Search for more papers by this author First published: June 1993 https://doi.org/10.1002/eqe.4290220606Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume22, Issue6June 1993Pages 547-547 RelatedInformation

International Journal of DermatologyVolume 26, Issue 1 p. 66-66 Meetings of International Interest SAMUEL B. FRANK M.D., SAMUEL B. FRANK M.D. EDITOR 3634 Seventh Avenue, 2D San Diego, CA 92103Search for more papers by this author SAMUEL B. FRANK M.D., SAMUEL B. FRANK M.D. EDITOR 3634 Seventh Avenue, 2D San Diego, CA 92103Search for more papers by this author First published: January 1987 https://doi.org/10.1111/j.1365-4362.1987.tb04582.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume26, Issue1January 1987Pages 66-66 RelatedInformation

International Journal of DermatologyVolume 22, Issue 1 p. 64-65 Meetings of International Interest SAMUEL B. FRANK M.D., SAMUEL B. FRANK M.D. EDITOR 3634 Seventh Avenue, 2D San Diego, CA 92103Search for more papers by this author SAMUEL B. FRANK M.D., SAMUEL B. FRANK M.D. EDITOR 3634 Seventh Avenue, 2D San Diego, CA 92103Search for more papers by this author First published: January 1983 https://doi.org/10.1111/j.1365-4362.1983.tb02119.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume22, Issue1January 1983Pages 64-65 RelatedInformation