Proteolysis-targeting chimeras mediate the degradation of bromodomain and extra-terminal domain proteins.

Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target's ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.

[A case report on treatment of compartment syndrome with novel coronavirus pneumonia].

A 49-year-old male patient with compartment syndrome of the right leg caused by acute carbon monoxide poisoning was admitted on December 30, 2019. The patient had a 10-year history of chronic nephritis and began dialysis treatment due to renal failure 1 month ago. Emergency surgical decompression for compartment syndrome was performed after admission. Two weeks later, the patient was diagnosed as the novel coronavirus pneumonia caused by 2019 novel coronavirus (2019-nCoV) infection. Then, the patient was transferred to the isolation ward, where he was given anti-infection, anti-virus, expectorant, heat-clearing and detoxifying drugs, bedside dialysis, and nutrition support symptomatic treatment. After 2 weeks of treatment, the patient is getting better, with no fever, cough, wheezing, and other discomfort. Meanwhile, the sensory and motor functions of right lower limb recovered gradually. This case is rare, severe, and difficult to diagnose and treat. It is the first reported case of novel coronavirus pneumonia after orthopedic surgery.

Luminescent Transparent Wood Based on Lignin-Derived Carbon Dots as a Building Material for Dual-Channel, Real-Time, and Visual Detection of Formaldehyde Gas.

Formaldehyde (FA) is a widespread indoor air pollutant, and its efficient detection is a major industrial challenge. The development of a building material with real-time and visual self-detection of FA gas is highly desirable for meeting both construction and human health demands. Herein, a luminescent transparent wood (LTW) as the building material was developed for dual-channel, real-time, and visual detection of FA gas. It was fabricated by encapsulating multicolor lignin-derived carbon dots (CDs) and poly(vinyl alcohol) (PVA) into a delignified wood framework. It exhibited 85% optical transmittance, tunable room-temperature phosphorescence (RTP), and ratiometric fluorescence (FL) emission. The tunable luminescence was attributed to different CD graphitization and surface functionalization. The color-responsive ratiometric FL and delayed RTP detections of FA were displayed over the range of 20-1500 µM (R2 = 0.966, LOD = 1.08 nM) and 20-2000 µM (R2 = 0.977, LOD = 45.8 nM), respectively. The LTW was also used as an encapsulation film on a UV-emitting InGaN chip to form white light-emitting diodes, indicating the feasibility as an FA-responsive planar light source. The operational notion of functional LTW can expand its applications to new fields such as a stimuli-responsive light-transmitting window or planar light sources while monitoring indoor air pollutants, temperature, and humidity.

Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide.

BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 µM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis.

It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

Leucocyte Membrane-Coated Janus Microcapsules for Enhanced Photothermal Cancer Treatment.

Polyelectrolyte multilayer (PEM) capsules are promising candidates for many kinds of cancer detection and treatment but are usually intended to deliver cargo to specific sites or to destroy cancer cells based on photothermal effects from the outside. In this publication we prove that it is possible to kill cancer cells from the inside based on phagocytosed PEM capsules. In addition we show how to open the cells and bring the PEM capsules to the surface of cancer cells based on photothermal effects and rapid evaporation of water. Diffusion-based temperature determinations of the photothermal effect up to the evaporation temperature of water are presented.

How Leucocyte Cell Membrane Modified Janus Microcapsules are Phagocytosed by Cancer Cells.

Modern drug delivery systems rely on either antibody-based single-surface recognition or on surface-hydrophobicity-based approaches. For a tumor showing various surface mutations, both approaches fail. This publication hereby presents Janus capsules based on polyelectrolyte multilayer microcapsules exhibiting human leucocyte (THP-1 cell line) cell membranes for discriminating HUVEC cells from three different cancer cell lines. Despite destroying the cellular integrity of leucocyte cells, the modified Janus capsules are able to adhere to cancer cells. Leucocyte cell-membrane-coated Janus capsules are phagocytosed with the cellular membrane part pointing to the cells.

Improved inhibitory activities against tumor-cell migration and invasion by 15-benzylidene substitution derivatives of andrographolide.

In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure-activity relationships were studied. Compared to 1, compounds 8a-8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.