Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.

Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-ß-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4',5'-f][1,3]diazepines.

Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC(50) values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1.

Novel, Broad Spectrum Anti-Cancer Agents Containing the Tricyclic 5:7:5-Fused Diimidazodiazepine Ring System.

Synthesis of a series of novel, broad-spectrum anti-cancer agents containing the tricyclic 5:7:5-fused diimidazo[4,5-d:4',5'-f][1,3]diazepine ring system is reported. Compounds 1, 2, 8, 11, and 12 in the series show promising in vitro antitumor activity with low micromolar IC(50)'s against prostate, lung, breast, and ovarian cancer cell lines. Some notions about structure-activity relationships and a possible mechanism of biological activity are presented. Also presented are preliminary in vivo toxicity studies of 1 using SCID mice.

WITHDRAWN: Derivatives of cis-1,2,3,6-tetrahydrophthalimide for the treatment of benign prostatic hyperplasia.

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An efficient synthesis of 2-amino alcohols by silica gel catalysed opening of epoxide rings by amines.

Silica gel (60-120 mesh) efficiently catalyses the opening of epoxide rings by amines at rt under solvent-free conditions providing an easy method for the synthesis of 2-amino alcohols. Aromatic and aliphatic amines react with cyclohexene oxide with exclusive formation of the trans-2-aryl/alkylaminocyclohexanols in high yields. A complementary regioselectivity is exhibited by aromatic and aliphatic amines during the reaction with styrene oxide. The epoxide ring of non-styrenoidal unsymmetrical alkene oxide undergoes selective nucleophilic attack at the sterically less hindered carbon by aniline.