Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7).

Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation.

Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Glucocorticoid activates STAT3 and NF-κB synergistically with inflammatory cytokines to enhance the anti-inflammatory factor TSG6 expression in mesenchymal stem/stromal cells.

Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.

The efficacy and safety of microwave ablation versus conventional open surgery for the treatment of papillary thyroid microcarcinoma: a systematic review and meta-analysis.

Background: Microwave ablation (MWA) technology has been applied to the treatment of papillary thyroid microcarcinoma (PTMC); however, its use as an alternative to conventional open surgery (OS) remains controversial, because it belongs to non-tumor radical treatment. Our article sought to compare the efficacy and safety of MWA and OS in the treatment of PTMC. Methods: We searched seven databases for studies evaluating the treatment of patients with PTMC using MWA as intervention group and OS as control group, the main outcome contained intra-operative, post-operative and follow-up outcomes. Review Manager 5.4 was used to estimate the effects of the results of the included articles and Cochrane Risk of Bias 2.0 was used to assess the risk of bias. The data were pooled to calculate the mean differences (MD) with 95% confidence intervals (CIs) for the continuous data and the odds ratio (OR) with 95% CIs for the dichotomous data. Results: A total of 13 studies, comprising 1,088 and 1,081 patients in the MWA and OS groups, respectively, were identified that compared the results of MWA to OS in the treatment of PTMC. All of the articles were at low risk of bias. There were no differences in terms of the recurrence rate (OR =0.80, 95% CI: 0.37 to 1.77; P=0.59) or lymph node metastasis (OR =0.71, 95% CI: 0.26 to 1.95; P=0.51) between the 2 groups. However, compared to the OS group, the MWA group had a shorter operation time (MD =-44.85, 95% CI: 5.73 to 20.68; P<0.00001), less intra-operative blood loss (MD =-23.37, 95% CI: -29.57 to -17.17; P<0.00001), a smaller surgical incision (MD =-47.04, 95% CI: -81.93 to -12.14; P=0.008), a shorter postoperative hospital stay (MD =-4.19, 95% CI: -5.46 to -2.92; P<0.00001), lower hospitalization expenses (MD =-85.65, 95% CI: -133.86 to -37.45; P<0.00001), and fewer complications (OR =0.23, 95% CI: 0.16 to 0.33; P<0.00001). Conclusions: This meta-analysis suggests that MWA is better than OS at treating PTMC in terms of both intra-operative and post-operative outcomes. Due to the quality and number of the included studies, the long-term effects and suitability of MWA in the treatment of PTMC need to be further studied.

Physical properties and antibacterial activity of the composited films based on carboxymethyl cellulose and gelatin functionalized with ε-polylysine.

Antibacterial composite films were produced from carboxymethyl cellulose-gelatin (CMC-Gel) blend with different concentration of ε-polylysine (ε-PL) and their physical and chemical properties were characterized. Compared with the control CMC-Gel film, the functionalized films had almost indistinguishable crystalline type, thickness, tensile strength, and elongation at break, however, poor water vapor barrier properties. The results showed that the ε-PL was well incorporated into CMC-Gel matrix by electrostatic interaction, as the changes of absorption peaks in the Fourier transform infrared spectrometer and the increase of glass transition temperature in differential scanning calorimeter. The films containing ε-PL showed excellent antibacterial activity against S. aureus, B. subtilis, E. coli and P. aeruginosa. In the composting experiment, the films become degraded on the seventh day, and further degraded with the growth of molds over time. The present results showed that the active films could be a potential material for food packaging.