Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.

Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα+) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα+ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer.

Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

Nanoscale Bouligand Multilayers: Giant Circular Dichroism of Helical Assemblies of Plasmonic 1D Nano-Objects.

Chirality is found at all length scales in nature, and chiral metasurfaces have recently attracted attention due to their exceptional optical properties and their potential applications. Most of these metasurfaces are fabricated by top-down methods or bottom-up approaches that cannot be tuned in terms of structure and composition. By combining grazing incidence spraying of plasmonic nanowires and nanorods and Layer-by-Layer assembly, we show that nonchiral 1D nano-objects can be assembled into scalable chiral Bouligand nanostructures whose mesoscale anisotropy is controlled with simple macroscopic tools. Such multilayer helical assemblies of linearly oriented nanowires and nanorods display very high circular dichroism up to 13 000 mdeg and giant dissymmetry factors up to g ≈ 0.30 over the entire visible and near-infrared range. The chiroptical properties of the chiral multilayer stack are successfully modeled using a transfer matrix formalism based on the experimentally determined properties of each individual layer. The proposed approach can be extended to much more elaborate architectures and gives access to template-free and enantiomerically pure nanocomposites whose structure can be finely tuned through simple design principles.

Enhancing PET hydrolytic enzyme activity by fusion of the cellulose-binding domain of cellobiohydrolase I from Trichoderma reesei.

The large amounts of polyethylene terephthalate (PET) that enter and accumulate in the environment have posed a serious threat to global ecosystems and human health. A PET hydrolase from PET-assimilating bacterium Ideonella sakaiensis (IsPETase) that exhibits superior PET hydrolytic activity at mild conditions is attracting enormous attention in development of plastic biodegrading strategies. In order to enhance the PET hydrolysis capacity of IsPETase, we selected several polymer-binding domains that can adhere to a hydrophobic polymer surface and fused these to a previously engineered IsPETaseS121E/D186H/R280A (IsPETaseEHA) variant. We found that fusing a cellulose-binding domain (CBM) of cellobiohydrolase I from Trichoderma reesei onto the C-terminus of IsPETaseEHA showed a stimulatory effect on enzymatic hydrolysis of PET. Compared to the parental enzyme, IsPETaseEHA_CBM exhibited 71.5 % and 44.5 % higher hydrolytic activity at 30 ℃ and 40 ℃, respectively. The catalytic activity of IsPETaseEHA_CBM was increased by 86 % when the protein concentration was increased from 2.5 µg/mL to 20 µg/mL. These findings suggest that the fusion of polymer-binding module to IsPETase is a promising strategy to stimulate the enzymatic hydrolysis of PET.

In-plane aligned assemblies of 1D-nanoobjects: recent approaches and applications.

One-dimensional (1D) nanoobjects have strongly anisotropic physical properties which are averaged out and cannot be exploited in disordered systems. The goal of the present review is to describe the current methods for preparing macroscopic composite films in which the long axis of individual 1D-nanoobjects is more or less parallel to the x,y-plane of the substrate as well as to each other (alignment direction). Such structures are generally described as in-plane anisotropic and many of their physical properties show minima or maxima parallel to the alignment direction. Optical polarizers are a typical class of such materials, but anisotropic materials properties can enhance the performance of devices and materials over many length scales in various disciplines of materials science including electronic devices, environmental sensors, energy saving and energy generation applications, plasmonic devices, Surface-Enhanced Raman Scattering (SERS) and biological applications. The reviewed alignment methods fall into two categories: techniques in which all nanoobjects remain in the x,y-plane and the in-plane densities and alignment are controlled; and techniques allowing building complex architectures in which each stratum of multilayered or stacked films may differ in chemical nature or alignment direction or both. This review serves a purpose to provide a platform to inspire new alignment approaches with improved assembly quality and upscaling potential and new applications with enhanced performance by alignment.

[Responses of wetland water quality to influence the strengthness of urbanization in Nanjing, China].

28 typical wetlands were selected to monitor the contaminants in water monthly, that influenced by urbanization in different scales. On the other hand, the land use types such as impervious area and forest area in the catchments of urban wetlands were analyzed by GIS and landscape ecology. And then the effects of urbanization index (UEI) was employed to reveal the relationship between urbanization level and water quality in Xianlin New City of Nanjing. Results indicated that: (1) the seasonal variations of water quality showed that water quality in summer was worse than those in other seasons, and the water quality in winter was good. However there were no significant differences between the spring and the autumn. (2) the relationship was significant between urbanization level and water quality, and the water quality tended to be getting worse when the urbanization level was getting higher. The concentrations of TP, TN, NH(4+)-N, and Chla were 0.27, 1.07, 0.15 and 17.94 mg x L(-1) respectively in the high urbanization (HU) level wetland while the concentrations were 0.12, 0.56, 0.12 and 4.85 mg x L(-1) in the low urbanization (LW) level wetland. (3) there was a threshold between UEI and the water quality. On the whole, the water quality would get worse quickly when the value of UEI exceeded 2.2.

[Influence of spatial difference on water quality in Jiuxiang River watershed, Nanjing].

Exploring the quantitative relationship between landscape characteristics and surface water quality indicators can provide important information to urban landscape planning and water environment protection. Jiuxiang River watershed in Nanjing city, being as a typical case study area, its landscape classification maps was conducted in 2009 by remote sensing digital images interpretation. Based on the remote sensing images and real-time monitoring data from October 2009 to September 2010, geospatial analysis and statistical analysis were integrated to explore the relationship between landscape composition, landscape pattern (landscape-level and class-level) and river water quality at the subwatershed scale. Results showed that most of landscape compositions influenced river water quality. Percentage of built-up land and unused land was positively related to total nitrogen (TN), total phosphorus (TP), ammonia nitrogen (NH4(+) -N) and permanganate index, while percentage of forestland showed a negative relationship. At the landscape level, the water quality was good when the size of patch was big. But at class-level, the aggregated distribution of the built-up land, unused land and arable land might cause TN, TP, permanganate index and NH4(+) -N concentration increased. But the aggregated distribution of the forestland had the opposite effect on water quality indicators.

Novel complex hydrogels based on N-carboxyethyl chitosan and quaternized chitosan and their controlled in vitro protein release property.

A novel pH-responsive hydrogel (CHC) composed of N-carboxyethyl chitosan (CEC) and N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) was synthesized by the redox polymerization technique. Turbidimetric titrations were used to determine the stoichiometric ratio of these two chitosan derivatives. The hydrogel was characterized by FT-IR, thermal gravimetric analysis (TGA), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). The dynamic transport of water showed that the hydrogel reached equilibrium within 48h. The swelling ratio of CHC hydrogel depended significantly on the pH of the buffer solution. The performance of the CHC as a matrix for the controlled release of BSA was investigated. It was found that the release behavior was determined by pH value of the medium as well as the intermolecular interaction between BSA and the hydrogels.