Design, Synthesis, and Antitumor Activity Evaluation of Proteolysis-Targeting Chimeras as Degraders of Extracellular Signal-Regulated Kinases 1/2.

Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 µM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.

Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5.

Extracellular signal-regulated kinase 5 (ERK5) is recognized as a key member of the mitogen-activated protein kinase family and is involved in tumor growth, migration, and angiogenesis. However, the results of ERK5 inhibition in multiple studies are controversial, and a highly specific ERK5-targeting agent is required to confirm physiological functions. Using proteolysis-targeting chimera technology, we designed the selective ERK5 degrader PPM-3 and examined its biological effect on cancer cells. Interestingly, the selective degradation of ERK5 with PPM-3 did not influence tumor cell growth directly. Based on proteomics analysis, the ERK5 deletion may be associated with tumor immunity. PPM-3 influences tumor development by affecting the differentiation of macrophages. Therefore, PPM-3 is an effective small-molecule tool for studying ERK5 and a promising immunotherapy drug candidate.

A Computational Model of Cn2 Profile Inversion for Atmospheric Laser Communication in the Vertical Path.

In this paper, an atmospheric structure constant Cn2 model is proposed for evaluating the channel turbulence degree of atmospheric laser communication. First, we derive a mathematical model for the correlation between the atmospheric coherence length r0, the isoplanatic angle θ0 and Cn2 using the Hufnagel-Valley (HV) turbulence model. Then, we calculate the seven parameters of the HV model with the actual measured r0 and θ0 data as input quantities, so as to draw the Cn2 profile and the θ0 profile. The experimental results show that the fitted average Cn2 contours and single-day Cn2 contours have superior fitting performance compared with our historical data, and the daily correlation coefficient between the single-day computed θ0 contours and the measured θ0 contours is up to 87%. This result verifies the feasibility of the proposed method. The results validate the feasibility of the proposed method and provide a new technical tool for the inversion of turbulence Cn2 profiles.

Discovery and Biosynthesis of Pepticinnamins G-M Featuring Three Enzymes-Catalyzed Nonproteinogenic Amino Acid Formation.

Since pepticinnamin E was discovered almost 30 years ago, no other pepticinnamin family of natural products has been reported to date. Here, we report the discovery of pepticinnamins G-I (1-3) from a marine Streptomyces sp. PKU-MA01144 and pepticinnamins J-M (4-7) from several mutants, and these new compounds contain different N-methyl-l-alanine and l-tyrosine residues compared to pepticinnamin E. Genome sequencing, heterologous expression, gene deletion, and reconstitution of enzymatic reaction in vitro identified the biosynthetic gene cluster of 1-7 and first experimentally established the biosynthesis of the nonproteinogenic 2-chloro-3-hydroxy-4-methoxy-l-phenylalanine residue by a biopterin-dependent hydroxylase Pep10, an O-methyltransferase Pep9, and a flavin-dependent halogenase Pep1. The biosynthetic research and heterologous expression system in this study set the stage for pathway engineering for more pepticinnamins generation in the future.

Discovery of a Phenylamine-Incorporated Angucyclinone from Marine Streptomyces sp. PKU-MA00218 and Generation of Derivatives with Phenylamine Analogues.

A new phenylamine-incorporated angucyclinone (1) featuring a unique 1-phenylbenzo[ cd]indol-3(1 H)-one moiety was discovered from marine Streptomyces sp. PKU-MA00218. A series of experimental investigations identified that 1 was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine. Utilizing the nonenzymatic conversion, 18 phenylamine-incorporated angucyclinone derivatives with halogen, methyl, methoxy, and carboxy substitutions were efficiently generated under mild conditions. These results highlighted the impressive roles of nonenzymatic reactions in expanding the structural diversity of angucyclinones.

[Effect of Morinda officinalis Root and Its Salt-Processing Product on Energy Metabolism in Rats with Yang Deficiency].

Objective: To compare the effects of Morinda officinalis root and its salt-processing prodduct on rats with kidney yang deficiency from the viewpoint of energetic metabolism. Methods: The rat models for the kidney yang deficiency were established through the perfusion of methimazole. The models were treated with different dosages of Morinda officinalis root without woods and its salt-processing products extracts. The activity of liver glycogen,muscle glycogen,free fatty acid( NEFA),lipoprotein lipase( LPL),hepatic lipase( HL),liver and skeletal muscle Na+,K+ATPase,Ca2 +,Mg2 +ATPase,succinodehydrogenase( SDH) were measured by colormetric methods,and the coefficient of body fat were observed by weighing method. Results: Morinda officinalis root without woods and its saltprocessing products could improve the energetic metabolism of kidney yang deficiency of rats. The effects of salt-processing products were better than Morinda officinalis root without woods in the same dosage. Conclusion: The effect of invigorating the kidney and strengthening yang of Morinda officinalis were correlated with energetic metabolism. The correct processing-products of Morinda officinalis root should be chosen with the suitable measurements in clinic.