ABSTRACT
Aminoacyl-tRNA synthetase (ARS) interacting multifunctional protein2 (AIMP2) plays a vital role in protein synthesis. However, a splicing variant in which the second of the four exons of AIMP2 is deleted, inhibits the tumor suppression activity of AIMP2. Herein, we describe our discovery of series of potent AIMP2-DX2 inhibitors that are targeting lung cancer. Optimization of series using ligand-based drug design strategy led to discovery of compound 35, a potent AIMP2-DX2 inhibitor that is the most efficacious in H460 and A549 cells. This benzodioxane series may represent good starting points for further lead optimization of the identification potential drug candidates for the AIMP2-DX2 targeted treatment of lung cancer.
Subject(s)
Amino Acyl-tRNA Synthetases , Lung Neoplasms , A549 Cells , Cell Line, Tumor , Exons , Humans , Lung Neoplasms/pathology , Nuclear ProteinsABSTRACT
In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.
Subject(s)
Amides/chemistry , Antitubercular Agents/chemistry , Thiazoles/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Amides/therapeutic use , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Stability , Female , Half-Life , Humans , Mice , Mice, Inbred BALB C , Microsomes/metabolism , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis/pathologyABSTRACT
This study compared the results of a tuberculin skin test (TST) and a whole-blood interferon-gamma release assay (IGRA) to screen latent tuberculosis (TB) infection (LTBI) according to risk of TB exposure in South Korea. A cross-sectional comparison of 82 healthcare workers (HCWs) was performed from June 2009 to January 2010. Participants were grouped according to their risk for TB exposure: group 1, frequent and direct contact with active TB patients (n = 35); group 2, no known history of direct contact with active TB patients (n = 47). For the TST (10-mm induration cut-off), the positive response rate was 42.9% in group 1 and 34.0% in group 2 (p = 0.42). For the IGRA, the positive response rate was 40% in group 1 and 10.6% in group 2 (p = 0.002). Results obtained from the TST and the IGRA were not in significant agreement. The working duration of HCWs in TB-related departments was the only significant risk factor for LTBI (odds ratio 1.03; p = 0.031). Further, the IGRA can more accurately discriminate LTBI compared to the TST, based on the risk of TB exposure. These results suggest that the IGRA is diagnostically useful for LTBI in South Korean HCWs.
