Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3

Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 E3 ligases encoded by the human genome, just over 10 E3 ligases are currently utilized for TPD. Here, using the affinity-directed protein missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 E3 ligases for their ability to degrade 4 target proteins, K-RAS, STK33, β-catenin, and FoxP3, which were endogenously GFP-tagged. Several new E3 ligases, including CUL2 diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases can be taken forward for the development of small-molecule degraders, such as proteolysis targeting chimeras (PROTACs). As a proof of concept, we demonstrate that a KLHDC2-recruiting peptide-based PROTAC connected to chloroalkane is capable of degrading HALO-GFP protein in cells

Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer.

Engineered nanomaterials that produce reactive oxygen species on exposure to X- and gamma-rays used in radiation therapy offer promise of novel cancer treatment strategies. Similar to photodynamic therapy but suitable for large and deep tumors, this new approach where nanomaterials acting as sensitizing agents are combined with clinical radiation can be effective at well-tolerated low radiation doses. Suitably engineered nanomaterials can enhance cancer radiotherapy by increasing the tumor selectivity and decreasing side effects. Additionally, the nanomaterial platform offers therapeutically valuable functionalities, including molecular targeting, drug/gene delivery, and adaptive responses to trigger drug release. The potential of such nanomaterials to be combined with radiotherapy is widely recognized. In order for further breakthroughs to be made, and to facilitate clinical translation, the applicable principles and fundamentals should be articulated. This review focuses on mechanisms underpinning rational nanomaterial design to enhance radiation therapy, the understanding of which will enable novel ways to optimize its therapeutic efficacy. A roadmap for designing nanomaterials with optimized anticancer performance is also shown and the potential clinical significance and future translation are discussed