Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders.

WD40-repeat (WDR) domain proteins play a crucial role in mediating protein-protein interactions that sustain oncogenesis in human cancers. One prominent example is the interaction between the transcription factor MYC and its chromatin co-factor, WD40-repeat domain protein 5 (WDR5), which is essential for oncogenic processes. The MYC family of proteins is frequently overexpressed in various cancers and has been validated as a promising target for anticancer therapies. The recruitment of MYC to chromatin is facilitated by WDR5, highlighting the significance of their interaction. Consequently, inhibiting the MYC-WDR5 interaction has been shown to induce the regression of malignant tumors, offering an alternative approach to targeting MYC in the development of anticancer drugs. WDR5 has two protein interaction sites, the "WDR5-binding motif" (WBM) site for MYC interaction and the histone methyltransferases SET1 recognition motif "WDR5-interacting" (WIN) site forming MLL complex. Significant efforts have been dedicated to the discovery of inhibitors that target the WDR5 protein. More recently, the successful application of targeted protein degradation technology has enabled the removal of WDR5. This breakthrough has opened up new avenues for inhibiting the interaction between WDR5 and the binding partners. In this review, we address the recent progress made in targeting WDR5 to inhibit MDR5-MYC and MDR5-MLL1 interactions, including its targeted protein degradation and their potential impact on anticancer drug discovery.

Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo.

Oxidative stress due to abnormal accumulation of reactive oxygen species (ROS) is an initiator of a large number of human diseases, and thus, the elimination and prevention of excessive ROS are important aspects of preventing the development of such diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is an essential transcription factor that defends against oxidative stress, and its function is negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1). Therefore, activating NRF2 by inhibiting KEAP1 is viewed as a strategy for combating oxidative stress-related diseases. Here, we generated a cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), which we named SD2267, that induces the proteasomal degradation of KEAP1 and leads to NRF2 activation. As was intended, SD2267 bound to KEAP1, recruited CRBN, and induced the degradation of KEAP1. Furthermore, the KEAP1 degradation efficacy of SD2267 was diminished by MG132 (a proteasomal degradation inhibitor) but not by chloroquine (an autophagy inhibitor), which suggested that KEAP1 degradation by SD2267 was proteasomal degradation-dependent and autophagy-independent. Following KEAP1 degradation, SD2267 induced the nuclear translocation of NRF2, which led to the expression of NRF2 target genes and attenuated ROS accumulation induced by acetaminophen (APAP) in hepatocytes. Based on in vivo pharmacokinetic study, SD2267 was injected intraperitoneally at 1 or 3 mg/kg in APAP-induced liver injury mouse model. We observed that SD2267 degraded hepatic KEAP1 and attenuated APAP-induced liver damage. Summarizing, we described the synthesis of a KEAP1-targeting PROTAC (SD2267) and its efficacy and mode of action in vitro and in vivo. The results obtained suggest that SD2267 could be used to treat hepatic diseases related to oxidative stress.

Graphene Quantum Dots for Cell Proliferation, Nucleus Imaging, and Photoluminescent Sensing Applications.

We report a simple one-pot microwave assisted "green synthesis" of Graphene Quantum Dots (GQDs) using grape seed extract as a green therapeutic carbon source. These GQDs readily self-assemble, hereafter referred to as "self-assembled" GQDs (sGQDs) in the aqueous medium. The sGQDs enter via caveolae and clathrin-mediated endocytosis and target themselves into cell nucleus within 6-8 h without additional assistance of external capping/targeting agent. The tendency to self-localize themselves into cell nucleus also remains consistent in different cell lines such as L929, HT-1080, MIA PaCa-2, HeLa, and MG-63 cells, thereby serving as a nucleus labelling agent. Furthermore, the sGQDs are highly biocompatible and act as an enhancer in cell proliferation in mouse fibroblasts as confirmed by in vitro wound scratch assay and cell cycle analysis. Also, photoluminescence property of sGQDs (lifetime circa (ca.) 10 ns) was used for optical pH sensing application. The sGQDs show linear, cyclic and reversible trend in its fluorescence intensity between pH 3 and pH 10 (response time: ~1 min, sensitivity -49.96 ± 3.5 mV/pH) thereby serving as a good pH sensing agent. A simple, cost-effective, scalable and green synthetic approach based sGQDs can be used to develop selective organelle labelling, nucleus targeting in theranostics, and optical sensing probes.