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[Display omitted] • A series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors were designed and synthesized. • The representative compound 23n was identified as a potent, selective and SAM-competitive PRMT5 inhibitor with an IC 50 value of 8 nM. • Prodrug 36 was designed by using the Trimethyl Lock prodrug strategy and exhibited largely improved antiproliferative activity against Z-138 and MOLM-13 cell lines than compound 23n. Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC 50 value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell-based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and suppressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold. [ABSTRACT FROM AUTHOR]

A new multi-agent based congestion evacuation model incorporating panic behavior is proposed in this paper for simulating pedestrian evacuation in public places such as a stadium. Different from the existing results, pedestrians in this model are divided into four classes and each pedestrian’s status can be either normal, being overtaken, or casualty. The direction of action for each individual is affected by competitive ability, distance to the exits as well as number and density of occupants within the view field of the agent. Our simulations exhibit that during the evacuation process: (1) The agents gather in front of the exits spontaneously and present arched shapes close to the exits. (2) Under the panic state the agents cohere closely and almost do not change the target exit. So other alternative exits are ignored. (3) For the case without obstacle, the casualties under panic increase greatly. But if there are obstacles (chairs), the congestion can be alleviated. Thus the casualties are reduced. (4) If certain exit is partly clogged, the evacuation becomes more efficient when adding a virtual leader. The overall simulation results show that the proposed model can reproduce the real evacuation process in a stadium quite well. [ABSTRACT FROM AUTHOR]

The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors. [Display omitted] • A series of nucleoside-derived ring-opening PRMT5 Inhibitors were designed and synthesized. • The representative compounds A2 and A8 were identified as a potent, selective and SAM-competitive PRMT5 inhibitors. • A8 exhibited potent antitumor efficacy without the loss of body weight in MOLM-13 xenograft model. [ABSTRACT FROM AUTHOR]

N 6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions. [Display omitted] • WD6305, a potent METTL3-targeted PROTAC degrader, is developed • WD6305 selectively reduces the METTL3 and METTL14 complex • METTL3 degradation outperforms METTL3 inhibition in AML antiproliferation Du et al. discovered and characterized WD6305, a selective METTL3-targeted PROTAC. This compound effectively and selectively abolishes the METTL3 and METT14 complex. Their findings demonstrate that pharmacological degradation of METTL3-METTL14 complex surpasses its inhibition as a potential anti-leukemic strategy. [ABSTRACT FROM AUTHOR]

Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC 50 values of 1.43 and 0.94 μM in NCI–H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8 , but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI–H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer. [Display omitted] • A potent and selective PROTAC degrader of NSD3 was designed, synthesized and evaluated. • Compound 8 decreased NSD3-associated genes and H3K36me3. • Compound 8 induced lung cancer cell growth arrest and apoptosis. • Compound 8 inhibited proliferation and clone formation in lung cancer cells. • A single dose of compound 8 effectively reduced NSD3 in xenograft tumor tissue in mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of p300 bromodomain inhibitors with new scaffolds was discovered based on bioisosterism and conformational restriction strategies. • Compounds 1u showed improved p300 bromodomain inhibitory activity and anti-proliferative activity in OPM-2 human myeloma cell line compared to CBP30. • Western blotting analysis showed that 1u suppressed the expression of c-Myc. • Mechanism studies indicated that 1u induced G 1 /G 0 phase arrest and apoptosis in OPM-2 cells. Adenovirus E1A-associated 300-k D protein (p300) bromodomain, which regulates gene expression by recognizing acetylated lysine (KAc) of histone, is a promising target for the treatment of cancer. Herein, a series of potent p300 bromodomain inhibitors with novel CBP30-based scaffolds was discovered through bioisosterism and conformational restriction strategies. The most promising compound 1u showed more potent inhibitory activity (IC 50 = 49 nM) against p300 bromodomain and anti-proliferative activity in various cancer cell lines compared to CBP30. Moreover, 1u suppressed the expression of c-Myc and induced G 1 /G 0 phase arrest and apoptosis in OPM-2 cells more potently than CBP30. This study provides new lead compounds for further research on the biological functions of p300. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of p300 bromodomain inhibitors were discovered and more tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. • Compound B4 showed potent p300 bromodomain inhibitory activity and improved proliferation inhibition on sensitive tumor cells than CCS1477. • Compound B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. • Compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk. p300/CBP bromodomain plays an important role in transcriptional regulation, and its overexpression is closely related to various diseases such as cancers. Two inhibitors of this target are currently in clinical trials but only CCS1477 (A1) have been published with the chemical structure. Herein, we modified the structure of CCS1477 based on the principle of bioisosterism and reasonable scaffold hopping, and discovered a series of new p300 bromodomain inhibitors with improved potency. More tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. Among our new inhibitors, (R)-5-methylpyrrolidin-2-one derivitive B4 was the most potent one which showed comparable inhibitory activity against p300 (IC 50 = 0.060 μM) as lead A1 (IC 50 = 0.064 μM) at molecular level, and performed more potent proliferation inhibitory activities on various tumor cells than A1. Further we found that compound B4 had the high cell permeability and overcame the defect of the high efflux rate of A1 , which could also explain the possible reason why B4 showed more potent inhibitory activities on sensitive tumor cells than lead A1. Western blotting analysis proved the target effects that B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. Liver microsomal metabolic stability assay and hERG channel inhibition evaluation illustrate compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk, which further demonstrate the good drug-likeness of B4. Therefore, compound B4 is a promising compound for further optimization and development. [ABSTRACT FROM AUTHOR]

Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC 50 = 2.7 μM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice. [Display omitted] • 5-aminonaphthalene derivatives were designed, synthesized and evaluated, the SAR of these compounds was demonstrated. • Compound 9c exhibited a good NSD2 inhibitory activity and inhibited the proliferation of leukemia cell line. • The anti-cancer effect of 9c is partly achieved by suppressing the transcriptional activation of NSD2-targeted genes. • When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo. [ABSTRACT FROM AUTHOR]