DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

The location independence of learned attentional flexibility.

Individuals can adjust their shift readiness, known as attentional flexibility, according to the statistical structure of the environment. However, the extent to which these modulations in attentional flexibility are associated with a global readiness to shift attention to any location versus an anticipated shift to a single location remains unknown. Across two experiments, participants shifted attention among three rapid serial visual presentation (RSVP) streams of alphanumeric characters in response to embedded visual cues and made button presses in response to targets at the cued location. We manipulated the likelihood that participants would receive a cue that signaled a shift between two of the streams across blocks of trials. The likelihood of a cued shift of attention to the third location was held constant across all blocks. Participants demonstrated smaller target detection shift costs (Experiments 1 and 2) and shorter saccade latencies (Experiment 1) when the overall likelihood of shifting was high than when the overall shift likelihood was low. Critically, we observed evidence of both global shift readiness and location-specific shift readiness in both experiments such that participants shifted attention to the most-likely-to-be cued location the fastest, but still demonstrated a difference in the time to shift attention to the unlikely location according to the overall shift likelihood. Our findings provide evidence that moment-by-moment changes in attentional flexibility are not limited to an expectation to shift to a single location, but rather reflect, in part, a location-independent state of control.

Humidity sensors based on molecular rectifiers.

Ambient humidity plays a key role in the health and well-being of us and our surroundings, making it necessary to carefully monitor and control it. To achieve this goal, several types of instruments based on various materials and operating principles have been developed. Reducing the production costs for such systems without affecting their sensitivity and reliability would allow for broader use and greater efficiency. Organic materials are prime candidates for incorporation in humidity sensors given their extraordinary chemical diversity, low cost, and ease of processing. Here, we designed, assembled and tested humidity sensors based on molecular rectifiers that can electrically transduce the changes in the ambient humidity to offer accurate quantitative information in the range of 0 to 70% relative humidity. Their operation relies on the changes occurring in the electric field experienced by the molecular layer upon absorption of the polar water molecules, resulting in modifications in the height and shape of the tunneling barrier. The response is reversible and reproducible upon multiple cycles and, coupled with the simplicity of the device architecture and manufacturing, makes these nanoscale sensors attractive for incorporation in various applications.