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Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism with therapeutic prospect for treating hyperlipidemia and various cancers. Much effort has been put into discovering ACLY inhibitors. However, current screening approaches have limitations in sensitivity, portability and high-throughput. To develop a general screening assay, we investigated series of conditions affecting the enzymatic reaction based on the ADP-Glo luminescence assay. Bovine serum albumin (0.001%) added triggered strong and stable fluorescence signal. The optimized assay was validated and applied to screen our natural product library. Two novel inhibitors were identified with IC

Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC

With the advantages of high-performance, easy to build and relatively low cost, the multigap resistive plate chamber has been arousing broad interests over the last few decades. It has become a new standard technology for the time of flight system in high energy physics experiments. In this article, we will give a description of the structure and the operating principles of the MRPC detector and focus on reviewing the applications on the time of flight system in several famous experiments. The performances, including time resolution and particle identification, are discussed in detail. Some recent advances and points of view for the future development of the next generation MRPC are also outlined.

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001, a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002, an analog of M1001, shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2.

The elevation of oxidative stress preferentially in cancer cells by efficient NQO1 substrates, which promote ROS generation through redox cycling, has emerged as an effective strategy for cancer therapy, even for treating drug-resistant cancers. Here, we described the identification and structural optimization studies of the hit compound 1, a new chemotype of nonquinone substrate for NQO1 as an efficient ROS generator. Further structure-activity relationship studies resulted in the most active compound 20k, a tricyclic 2,3-dicyano indenopyrazinone, which selectively inhibited the proliferation of NQO1-overexpressing A549 and A549/Taxol cancer cells. Furthermore, 20k dramatically elevated the intracellular ROS levels through NQO1-catalyzed redox cycling and induced PARP-1-mediated cell apoptosis in A549/Taxol cells. In addition, 20k significantly suppressed the growth of A549/Taxol xenograft tumors in mice with no apparent toxicity observed in vivo. Together, 20k acts as an efficient NQO1 substrate and may be a new option for the treatment of NQO1-overexpresssing drug-resistant NSCLC.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2α (HIF-2α) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2α inhibitors to the promising potency of the HIF-2α inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2α has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2α in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2α allosteric inhibitors.

Over the last ten years, muon imaging has attracted much attention due to its possible applications to detect high-Z materials in shipping containers or image very large objects such as volcanoes and large buildings. Precise measurements of the incident and outgoing angles of the cosmic muons are mandatory in this application. Large size (M)RPC detector with sub-millimetre position resolution should be an ideal candidate for the detector system. Prior work on improving the position resolution of MRPC mainly focuses on adjusting read-out panel and the detector geometry, while little work has been done on improving the position reconstruction algorithm. This paper proposes a new position reconstruction algorithm based on the neural networks which has no systematic error and gives better results than the center of gravity algorithm.

TOF (Time Of Flight) system based on MRPC (Multi-gap Resistive Plate Chamber) technology is widely used in modern physics experiments, and it also plays an important role in particle identification. With the increase of accelerator energy and luminosity, the TOF system is required to identify definite particles precisely under high rate environment. The MRPC technology TOF system can be defined as three generations. The first generation TOF is based on float glass MRPC and its time resolution is around 80 ps, but the rate is relatively low (typically lower than a few hundred Hz/cm2). The typical systems are TOF of RHIC-STAR, LHC-ALICE and BES III endcap. For the second generation TOF, its time resolution is in the same order with the first generation, but the rate capability is much higher. Its rate capability can reach 30 kHz/cm2. The typical experiment with this high rate TOF is FAIR-CBM. The biggest challenge is on the third generation TOF. For example, the momentum upper limit of K/PI separation is around 7 GeV/c for JLab-SoLID TOF system under high particle rate as high as 20 kHz/cm2, the time requirement is around 20 ps. The readout electronics of the first two generations is based on time over threshold method and pulse shape sampling technology will be used in the third generation TOF. In the same time, the machine learning technology is also designed to analyze the time performance. In this paper, we will describe the evolution of MRPC TOF technology and key technology of each generation TOF.

Multi-gap Resistive Plate Chamber(MRPC) is a widely used timing detector with a typical time resolution of about 60 ps. This makes MRPC an optimal choice for the time of flight(ToF) system in many large physics experiments. The prior work on improving the time resolution is mainly focused on altering the detector geometry, and therefore the improvement of the data analysis algorithm has not been fully explored. This paper proposes a new time reconstruction algorithm based on the deep neural networks(NN) and improves the MRPC time resolution by about 10 ps. Since the development of the high energy physics experiments has pushed the timing requirements for the MRPC to a higher level, this algorithm could become a potential substitution of the time over threshold(ToT) method to achieve a time resolution below 30 ps., 6 pages, 3 figures

The measurement of the $K^{\pm}$ production in the Semi-Inclusive Deep Inelastic Scattering (SIDIS) can provide further knowledge about the structure of nucleon, and thus it is purposed in the Solenoidal Large Intensity Device(SoLID) at Jefferson Lab(JLab). In this experiment, the identification of the kaons is planed to be accomplished with the Multi-gap Resistive Plate Chambers(MRPC), and the requirement for the time resolution is around 20 $\rm ps$. This is very challenging for the present MRPC systems (typical resolution 60 $\rm ps$), while in this paper, it is proved that the performance can be improved largely if the signal waveform is obtained and analyzed with a neural network method. In a cosmic ray experiment, the time resolution of a 6-gap 0.25$\rm mm$-thick MRPC reaches 36 $\rm ps$ with this method, and a even better performance is expected with a thinner MRPC., Comment: 9 pages, 7 figures