Current strategies and progress for targeting the "undruggable" transcription factors.

Transcription factors (TFs) specifically bind to DNA, recruit cofactor proteins and modulate target gene expression, rendering them essential roles in the regulation of numerous biological processes. Meanwhile, mutated or dysregulated TFs are involved in a variety of human diseases. As multiple signaling pathways ultimately converge at TFs, targeting these TFs directly may prove to be more specific and cause fewer side effects, than targeting the upfront conventional targets in these pathways. All these features together endue TFs with great potential and high selectivity as therapeutic drug targets. However, TFs have been historically considered "undruggable", mainly due to their lack of structural information, especially about the appropriate ligand-binding sites and protein-protein interactions, leading to relatively limited choices in the TF-targeting drug design. In this review, we summarize the recent progress of TF-targeting drugs and highlight certain strategies used for targeting TFs, with a number of representative drugs that have been approved or in the clinical trials as examples. Various approaches in targeting TFs directly or indirectly have been developed. Common direct strategies include aiming at defined binding pockets, proteolysis-targeting chimaera (PROTAC), and mutant protein reactivation. In contrast, the indirect ones comprise inhibition of protein-protein interactions between TF and other proteins, blockade of TF expression, targeting the post-translational modifications, and targeting the TF-DNA interactions. With more comprehensive structural information about TFs revealed by the powerful cryo-electron microscopy technology and predicted by machine-learning algorithms, plus more efficient compound screening platforms and a deeper understanding of TF-disease relationships, the development of TF-targeting drugs will certainly be accelerated in the near future.

Docking-guided rational engineering of a macrolide glycosyltransferase glycodiversifies epothilone B.

Glycosyltransferases typically display acceptor substrate flexibility but more stringent donor specificity. BsGT-1 is a highly effective glycosyltransferase to glycosylate macrolides, including epothilones, promising antitumor compounds. Here, we show that BsGT-1 has three major regions significantly influencing the glycodiversification of epothilone B based on structural molecular docking, "hot spots" alanine scanning, and site saturation mutagenesis. Mutations in the PSPG-like motif region and the C2 loop region are more likely to expand donor preference; mutations of the flexible N3 loop region located at the mouth of the substrate-binding cavity produce novel epothilone oligosaccharides. These "hot spots" also functioned in homologues of BsGT-1. The glycosides showed significantly enhanced water solubility and decreased cytotoxicity, although the glycosyl appendages of epothilone B also reduced drug permeability and attenuated antitumor efficacy. This study laid a foundation for the rational engineering of other GTs to synthesize valuable small molecules.

[Pollution Characteristics and Health Risk Assessment of Atmospheric VOCs in Chengdu].

Volatile organic compounds (VOCs) were measured in atmospheric samples collected from urban and roadside atmospheric environments in Chengdu in September 2012. The composition, chemical reactivity, and concentration level and its variation characteristics of VOCs were studied, and the health risk of aromatic compounds was assessed. Results showed that the mean mass concentrations of total VOCs (TVOCs) were (108.57±52.43) µg·m-3 and (132.61±49.31) µg·m-3 for the urban and roadside atmospheric environments, respectively. The highest mass concentrations were observed for alkanes, followed by aromatics, alkenes, and alkynes. Aromatics and alkenes contributed more to ozone formation potential (OFP) of the urban and roadside atmospheric environments, and m/p-xylene, toluene, ethene, o-xylene, and propene were the key reactive species. The values of hazard quotient and hazard index were less than 1 for benzene, toluene, ethylbenzene, and o-xylene (BTEX), showing that they had no appreciable risk of non-cancer health effects on the exposed population. However, the value of cancer risk was above the safety threshold for benzene, showing that it was a potential cancer risk to the exposed population.

Orthodontic treatment of a patient with cleidocranial dysplasia: A case report.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant condition that affects ossification. The dental abnormalities associated with CCD present an obstacle to orthodontic treatment planning. Early diagnosis is crucial to provide the patient with different treatment modalities that will suit the particular patient. In the present case, combined surgical and orthodontic treatment were performed to guide multiple impacted teeth. A single nucleotide missense variation was identified in exon 3 of runt-related transcription factor 2 (RUNX2) in this patient. The current results suggest a correlation between dental alterations and mutations in the runt domain of RUNX2 in CCD patients. Further clinical and genetic studies may required to confirm the association between phenotypes and genotypes in CCD and to identify other factors that may influence the clinical features of this disease. Patients with cleidocranial dysplasia require a team approach which demands good communication and cooperation from the patient. Timing of the intervention is critical, and numerous surgeries may be required. The patient in the present case report was treated by a team of practitioners, which involved several dental specialties to achieve an optimal result.