Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED-H3K27me3 Inhibitors for the Treatment of Lymphoma.

Interrupting the embryonic ectoderm development (EED)-H3K27me3 interaction represents a promising strategy to allosterically inhibit polycomb repressive complex 2 (PRC2) for cancer therapy. In this work, we report the structure-based design of new triazolopyrimidine-based EED inhibitors, which structurally feature the electron-rich indole ring at the C8 position. Particularly, ZJH-16 directly binds to EED (HTRF IC50 = 2.72 nM, BLI KD = 4.4 nM) and potently inhibits the growth of KARPAS422 and Pfeiffer cells. In both cells, ZJH-16 is selectively engaged with EED and reduces H3K27 trimethylation levels. ZJH-16 inhibits the gene silencing function of PRC2 in KARPAS422 cells. ZJH-16 possesses favorable pharmacokinetic (PK) profiles with an excellent oral bioavailability (F = 94.7%). More importantly, ZJH-16 shows robust tumor regression in the KARPAS422 xenograft model after oral administration with the tumor growth inhibition reaching nearly 100%. The robust antitumor efficacy and favorable PK profiles of ZJH-16 warrant further advanced preclinical development for lymphoma treatment.

Constructing brain functional network by Adversarial Temporal-Spatial Aligned Transformer for early AD analysis.

Introduction: The brain functional network can describe the spontaneous activity of nerve cells and reveal the subtle abnormal changes associated with brain disease. It has been widely used for analyzing early Alzheimer's disease (AD) and exploring pathological mechanisms. However, the current methods of constructing functional connectivity networks from functional magnetic resonance imaging (fMRI) heavily depend on the software toolboxes, which may lead to errors in connection strength estimation and bad performance in disease analysis because of many subjective settings. Methods: To solve this problem, in this paper, a novel Adversarial Temporal-Spatial Aligned Transformer (ATAT) model is proposed to automatically map 4D fMRI into functional connectivity network for early AD analysis. By incorporating the volume and location of anatomical brain regions, the region-guided feature learning network can roughly focus on local features for each brain region. Also, the spatial-temporal aligned transformer network is developed to adaptively adjust boundary features of adjacent regions and capture global functional connectivity patterns of distant regions. Furthermore, a multi-channel temporal discriminator is devised to distinguish the joint distributions of the multi-region time series from the generator and the real sample. Results: Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) proved the effectiveness and superior performance of the proposed model in early AD prediction and progression analysis. Discussion: To verify the reliability of the proposed model, the detected important ROIs are compared with clinical studies and show partial consistency. Furthermore, the most significant altered connectivity reflects the main characteristics associated with AD. Conclusion: Generally, the proposed ATAT provides a new perspective in constructing functional connectivity networks and is able to evaluate the disease-related changing characteristics at different stages for neuroscience exploration and clinical disease analysis.

Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors.

The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.

Design and synthesis of new indole containing biaryl derivatives as potent antiproliferative agents.

A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 µM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.

New drug approvals for 2020: Synthesis and clinical applications.

53 New drugs including 38 chemical entities and 15 biologics were approved by the U.S. Food and Drug Administration during 2020. Among the marketed drugs, 34 new small molecule drugs and 4 new diagnostic agents with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 34 small-molecule drugs newly approved by the FDA in 2020.

Cu(OTf)2-Catalyzed Intramolecular Radical Cascade Reactions for the Diversity-Oriented Synthesis of Quinoline-Annulated Polyheterocyclic Frameworks.

Compound libraries with high levels of structural diversity and novelty could cover underexploited chemical space and thus have been highly pursued in drug discovery. Herein, we report the first Cu(OTf)2-catalyzed intramolecular radical cascade reactions that enable the diversity-oriented synthesis of quinoline-annulated polyheterocyclic compounds (7 unique scaffolds, 66 examples) in an efficient manner. This work demonstrates an alternative route to access the natural product- and druglike compound collection with high levels of structural diversity and novelty.

Enolase 1 over-expression promotes proliferation and migration of lung cancer PC14 cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect of enolase 1 (ENO1) expression on proliferation, apoptosis and migration of lung cancer PC14 cells. Methods: ENO1 over-expression vector-pcDNA3.1/ENO1 was constructed and transfected into PC14 cells at logarithmic growth phase with liposome LipofectamineTM 2000. G418 was used to screen PC14 cells that stably expressing ENO1. The effects of ENO1 over-expression on proliferation, migration and apoptosis of PC14 cells were detected by CCK-8 method, scratch-healing assay and flow cytometry, respectively. Results: The ENO1 over-expression cell model was successfully constructed. Compared with PC14-vehicle and wild-type PC14 cells, the mRNA and protein expression levels of ENO1 in PC14-ENO1 cells were significantly elevated (all P<0.05), and the proliferation of PC14-ENO1 cells was significantly increased (all P<0.05). The relative mobility of PC14ENO1 cells was significantly higher than that of pcDNA3.1-vehicle cells and wild-type PC14 cells ([13.26±1.13]% vs [8.46±1.11]%, [7.86±1.00]%, both P<0.05). There was no significant difference in apoptotic rate among PC14-ENO1, PC14-vehicle and PC14 cells (all P> 0.05) Conclusion: Over-expression of ENO1 promotes proliferation and migration of lung cancer PC14 cells.

The type 1 transmembrane glycoprotein B7-H3 interacts with the glycolytic enzyme ENO1 to promote malignancy and glycolysis in HeLa cells.

The role of the type 1 transmembrane glycoprotein B7-H3 is controversial in tumorigenesis; thus, a better clarification of its involvement in cancer is crucial. In the present study, 79.3% of cervical cancer samples were found to be B7-H3 positive and the expression of B7-H3 was positively correlated with the clinical features of the samples. Silencing B7-H3 using small interfering RNA or blocking it with intracellular ScFv attenuated the malignancy of HeLa cells. By pull-down assay and liquid chromatography-mass spectrometry in HeLa cells, the glycolytic enzyme ENO1 was found to interact with B7-H3. Subsequently, the involvement of B7-H3 in glycolysis was investigated. We observed decreases in the levels of ATP and lactate, as well as c-Myc and lactate dehydrogenase A, upon B7-H3 downregulation in HeLa cells. The results of the present study provide evidence for B7-H3 mediating tumor glycolysis.

Generation of Hutat2:Fc Knockin Primary Human Monocytes Using CRISPR/Cas9.

The ability of monocytes to travel through the bloodstream, traverse tissue barriers, and aggregate at disease sites endows these cells with the attractive potential to carry therapeutic genes into the nervous system. However, gene editing in primary human monocytes has long been a challenge. Here, we applied the CRISPR/Cas9 system to deliver the large functional Hutat2:Fc DNA fragment into the genome of primary monocytes to neutralize HIV-1 transactivator of transcription (Tat), an essential neurotoxic factor that causes HIV-associated neurocognitive disorder (HAND) in the nervous system. Following homology-directed repair (HDR), ∼10% of the primary human monocytes exhibited knockin of the Hutat2:Fc gene in the AAVS1 locus, the "safe harbor" locus of the human genome, without selection. Importantly, the release of Hutat2:Fc by these modified monocytes protected neurons from Tat-induced neurotoxicity, reduced HIV replication, and restored T cell homeostasis. Moreover, compared with lentiviral transfection, CRISPR-mediated knockin had the advantage of maintaining the migrating function of monocytes. These results establish CRISPR/Cas9-mediated Hutat2:Fc knockin monocytes and provide a potential method to cross the blood-brain barrier for HAND therapy.

The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection.

Type-I interferons (IFN-I) are a widely expressed family that could promote antivirus immunity in the process of pathogens invasion. In a human immunodeficiency virus 1 (HIV-1)-infected individual, the production of IFN-I can be detected as early as the acute phase and will persist throughout the course of infection. However, sustained stimulation of immune system by IFN-I also contributes greatly to host-mediated immunopathology and diseases progression. Although the protective effects of IFN-I in the acute phase of HIV-1 infection have been observed, more studies recently focus on their detrimental role in the chronic stage. Inhibition of IFN-I signaling may reverse HIV-1-induced immune hyperactivation and furthermore reduce HIV-1 reservoirs, which suggest this strategy may provide a potential way to enhance the therapeutic effect of antiretroviral therapy. Therefore, we review the role of IFN-I in HIV-1 progression, their effects on different immunocytes, and therapeutic prospects targeting the IFN-I system.