Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial.

Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice.

AMP-activated protein kinase (AMPK) is an energy sensor of metabolism that is an attractive therapeutic target for type 2 diabetes mellitus and metabolic syndrome. Using a homogeneous scintillation proximity assay (SPA), we identified a new small-molecule AMPK activator, ZLN024, which allosterically stimulated active AMPK heterotrimers and the inactive α1 subunit truncations α1 (1-394) and α1 (1-335) but not α1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Cα.

Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase.