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Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery. Targeted protein degradation strategies are promising avenues for drug development, but it is important to broaden the toolbox of E3 ligases that can be engaged. This study shows that alkenyl oxindole compounds act as novel E3 ligase ligands and recruit the CRL4-DCAF11 E3 ubiquitin ligase complex for substrate degradation. [ABSTRACT FROM AUTHOR]

Glioma is the most prevalent and deadly type of intracranial tumor. Understanding the molecular drivers and their underlying mechanisms in glioma development is urgently needed. EYA1 is a unique protein phosphatase that drives gliomagenesis, yet its substrates remain largely uncharacterized. In this study, we identify BCL2L12 (BCL2-like 12), a critical oncoprotein in glioma, as a novel substrate of EYA1 phosphatase in glioma cells. Our findings demonstrate that EYA1 dephosphorylates BCL2L12 at threonine-33 (T33), which in turn protects BCL2L12 from ubiquitination and subsequent proteasomal degradation. Our results indicate that BCL2L12 partially mediates the oncogenic roles of EYA1 in promoting glioma cell proliferation, highlighting the significance of EYA1's dephosphorylation of BCL2L12 in tumor progression. Moreover, we validate a positive correlation between EYA1 and BCL2L12 protein levels in glioma patient samples. In summary, our study reveals how EYA1-BCL2L12 interaction functions in glioma development, implicating EYA1 as a potential therapeutic target for glioma treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo . Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)