Hybrid molecule between platanic acid and LCL-161 as a yes-associated protein degrader.

Dysregulated yes-associated protein (YAP) is involved in several malignant cancers. However, discovering a druggable YAP inhibitor(s) is difficult because YAP itself does not have any enzymatic activity. In such cases, targeted protein degradation strategies based on hybrid molecules that bind to the target protein and an E3 ubiquitin ligase are useful for suppressing proteins that exhibit aberrant activation and/or excessive expression. Upon screening YAP-interacting small compounds, we identified HK13, a platanic acid, as a novel compound that interacts with YAP. Next, we synthesized hybrid compounds of platanic acid and LCL-161, which reportedly shows a high affinity for cIAP, one of E3 ubiquitin ligases. Among these compounds, HK24 possessed the ability to inhibit the growth of YAP overexpressing NCI-H290 cells. This inhibitory activity may be mediated by YAP degradation, although HK24 exhibited weak YAP degradation. Furthermore, we confirmed involvement of proteasome pathway in HK24-dependent YAP degradation by culturing NCI-H290 cells in the presence of a proteasome inhibitor. Therefore, it is possible that platanic acid is a potential candidate for molecular medicine targeting YAP.

Genomic Regions Involved in Differences in Eating and Cooking Quality Other than Wx and Alk Genes between indica and japonica Rice Cultivars.

BACKGROUND: In temperate rice cultivation regions, japonica rice cultivars are grown preferentially because consumers deem them to have good eating quality, whereas indica rice cultivars have high grain yields and strong heat tolerance but are considered to have poor eating quality. To mitigate the effects of global warming on rice production, it is important to develop novel rice cultivars with both desirable eating quality and resilience to high temperatures. Eating quality and agronomic traits were evaluated in a reciprocal set of chromosome segment substitution lines derived from crosses between a japonica rice cultivar 'Koshihikari' and an indica rice cultivar 'Takanari'. RESULTS: We detected 112 QTLs for amylose and protein contents, whiteness, stickiness, hardness and eating quality of cooked rice grains. Almost of 'Koshihikari' chromosome segments consistently improved eating quality. Among detected QTLs, six QTLs on chromosomes 1-5 and 11 were detected that increased whiteness and stickiness of cooked grains or decreased their hardness for 3 years. The QTLs on chromosomes 2-4 were not associated with differences in amylose or protein contents. QTLs on chromosomes 1-5 did not coincide with QTLs for agronomic traits such as heading date, culm length, panicle length, spikelet fertility and grain yield. Genetic effects of the detected QTLs were confirmed in substitution lines carrying chromosome segments from five other indica cultivars in the 'Koshihikari' genetic background. CONCLUSION: The detected QTLs were associated with differences in eating quality between indica and japonica rice cultivars. These QTLs appear to be widely distributed among indica cultivars and to be novel genetic factors for eating quality traits because their chromosome regions differed from those of the GBSSI (Wx) and SSIIa (Alk) genes. The detected QTLs would be very useful for improvement of eating quality of indica rice cultivars in breeding programs.

Narciclasine is a novel YAP inhibitor that disturbs interaction between YAP and TEAD4.

Yes-associated protein (YAP) is involved in development, cell growth, cell size, and homeostasis and plays a key role in the progression of various cancers. Among them, constitutive activation of YAP can often be observed in malignant mesothelioma, which arises in the pleura, peritoneum, and pericardium because of inactivation of the Hippo pathway. To date, however, only less-effective treatments such as chemotherapy, radiation therapy, and surgery are available for patients with malignant mesothelioma. In this study, we identified narciclasine as a novel YAP inhibitor that prevents YAP from interacting with TEAD4 because it competes with TEAD4 for binding to YAP. Furthermore, narciclasine could perturb the cell growth and colony formation of malignant mesothelioma NCI-H290 cells in addition to inhibiting their growth in nude mice. Therefore, narciclasine might be a potential seed for a novel antitumor drug against malignant mesothelioma and other cancers in which hyperactivation and/or overexpression of YAP are observed.