Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer

Abstract

DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to −5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.

DDX3 Modulates Neurite Development via Translationally Activating an RNA Regulon Involved in Rac1 Activation

“…Moreover, DDX3 interacts and/or colocalizes with eIF4F components (Lai et al, 2008;Soto-Rifo et al, 2012). DDX3/Ded1p may facilitate RNA unwinding during ribosomal scanning of mRNAs or induce local separation of structured regions to facilitate cap recognition and eIF4A-catalyzed unwinding (Marsden et al, 2006;Lai et al, 2008;Soto-Rifo et al, 2012). We previously determined a DDX3-responsive region in the Rac1 5Ј UTR that contains two extended RNA duplexes (Chen et al, 2015), and in our present study we found that this structural feature exists in the 5Ј UTR of Prkaca (Fig.…”

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

“…Several inhibitors of the ATPase activity of DDX3 have been recently identified (29)(30)(31)(32)(33)(34); however, an ATP-mimetic compound may have a low degree of selectivity in vivo because of the possibility of interacting with many targets (35).…”

DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

“…Furthermore, despite the characterization of several DEAD/DEAH proteins, few specific inhibitors targeting these ATP-dependent helicases have been developed. Several lines of evidence from earlier studies demonstrate that RNA helicase inhibitors are promising cancer drugs for the future (34,35). Clearly, the diversity of DEAD/DEAH helicases in promoting cancer development warrants a broader evaluation of this protein family and the rational design of their inhibitors.…”