Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC50 of ∼ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer

Late Triassic tectonic inversion in the upper Yangtze Block: insights from detrital zircon U–Pb geochronology from southwestern Sichuan Basin

The Sichuan Basin and the Songpan-Ganze terrane, separated by the Longmen Shan fold-and-thrust belt (the eastern margin of the Tibetan Plateau), are two main Triassic depositional centers, south of the Qinling-Dabie orogen. During the Middle – Late Triassic closure of the Paleo-Tethys Ocean the Sichuan Basin region, located at the western margin of the Yangtze Block, transitioned from a passive continental margin into a foreland basin. In the meantime, the Songpan-Granze terrane evolved from a marine turbidite basin into a fold-and-thrust belt. To understand if and how the regional sediment routing system adjusted to these tectonic changes, we monitored sediment provenance primarily by using detrital zircon U-Pb analyses of representative stratigraphic samples from the southwestern edge of the Sichuan Basin. Integration of the results with paleocurrent and published detrital zircon data from other parts of the basin identified a marked change in provenance. Early-Middle Triassic samples were dominated by Neoproterozoic (~700-900Ma) zircons sourced mainly from the northern Kangdian basement, whereas Late Triassic sandstones recorded a more diverse range of zircon ages, sourced from the Qinling, Longmen Shan and Songpan-Ganze terrane. This change reflects a major drainage adjustment in response to the Late Triassic closure of the Paleo-Tethys Ocean and significant shortening in the Longmen Shan thrust belt and the eastern Songpan-Ganze terrane. Further, by Late Triassic time, the uplifted northern Kangdian basement had subsided. Considering the eastward paleocurrent and depocenter geometry of the Upper Triassic deposits, subsidence of the northern Kangdian basement probably resulted from eastward shortening and loading of the Songpan-Ganze terrane over the western margin of the Yangtze Block in response to the Late Triassic collision between Yangtze Block, Yidun arc and Qiangtang terrane along the Ganze-Litang and Jinshajiang sutures

Analysis of oxovanadium(IV) complexes using electrospray mass spectrometry: Molecular ion formed by loss of an electron, and its product ions trapping oxygen

Rationale: In addition to their biological properties, oxovanadium complexes have been widely applied as catalysts because of their excellent catalytic-oxidation capability. Recently, monometallic oxovanadium(IV) complexes have been used as catalysts in the electrophilic trifluoromethylation of silyl ketene imines. The study of catalysts can contribute to an understanding of the reaction mechanism. Methods: Six monometallic oxovanadium(IV) complexes were analyzed by electrospray ionization time-of flight mass spectrometry (ESI-TOFMS), and collision-induced dissociation mass spectrometry (CID-MS) experiments were conducted for selected cations [M](+) of oxovanadium(IV) complexes as well as a deuterium-labeled complex. Different collision gases were used to understand the source of the O-2 and H2O engaged in the gas-phase ion-molecule reaction. Results: The oxovanadium(IV) complexes formed [M](+) ions by loss of an electron, with [M + 14](+) ions being formed from [M](+) by loss of H2O and addition of O-2. The fragmentation pathways of the [M](+) cations were further studied by ESI-MS/MS, and several ions produced by gas-phase ion-molecule reactions were detected and characterized, including vanadium-oxo, -peroxo and derivatives. Conclusions: Several unexpected ions were detected, including [M](+), [M + 14](+) and ions produced from gas-phase ion-molecule reactions. The study has contributed to the understanding of the structure and character of oxovanadium(IV) complexes, and it could facilitate the design of new oxovanadium catalysts and an understanding of their reaction mechanism

DataSheet10_Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells.ZIP

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC50 of ∼ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer.</p

DataSheet7_Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells.ZIP

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC50 of ∼ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer.</p