Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients.

Inhibiting RORγt/Th17 axis for autoimmune disorders.

The recent success reported in late-stage clinical trials for the treatment of psoriasis by antibodies directed against interleukin (IL)-17 or its receptor has validated and strongly supports the development of inhibitors of the IL-17 pathway as a new therapeutic modality in chronic inflammation and autoimmunity. These results also encourage the drug discovery of orally available small molecules that can modulate down the production of IL-17 by Th17 cells (the major IL-17 producers) or the downstream signaling of the IL-17 receptor. Here, we review these strategies with an emphasis on inhibiting the retinoic-acid-related orphan nuclear receptor RORγt, which is the master regulator of Th17 cells and a promising therapeutic target for the treatment of multiple autoimmune disorders.

Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production.

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation.