ABCA1 modulators(University of Arizona)

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-β pathology.

Over-expressions of epidermal growth factor receptor and vascular endothelial growth factor receptor were frequently associated with the metastasis of solid tumors. Vandetanib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor and vascular endothelial growth factor receptor, was broadly effective in treating a variety of human solid tumors. The compelling evidence that hypoxia is involved in tumor resistance to cancer therapy. Hypoxia-inducible factor (HIF-1α), a major transcription factor in response to hypoxia, has been considered as a promising specific target for cancer therapy. We reported a stronger vandetanib derivative, compound 39, which was more potently decreased viability of A549, HT-29, MCF-7, HepG2, and HeLa cells than its parent compound vandetanib. Remarkable hypoxia-selectivity was observed in A549 cells (IC₅₀ = 1.55 ± 0.23 μM under normoxia and 0.31 ± 0.06 μM under hypoxia, respectively) and HT-29 cells (IC₅₀ = 12.89 ± 2.15 μM under normoxia and 3.47 ± 0.79 μM under hypoxia, respectively). The apoptosis of A549 and HT-29 cells induced by compound 39 were detected by flow cytometry. Western blot analysis demonstrated that compound 39 significantly down-regulated the anti-apoptotic B-cell lymphoma-2 (BCL-2) protein and up-regulated the expression of pro-apoptotic BCL2-Associated X (Bax) protein as well as promoted the cleavage of poly (ADP-ribose) polymerase PARP. HIF-1α was down-regulated by compound 39 in A549 and HT-29 cells under hypoxia. We also found that the depletion of intracellular Reduced Glutathione (GSH) as well as production of Reactive Oxygen Species (ROS) were critical for compound 39-mediated cell death.