- Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity
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MLL1-WDR5 interaction is essential for the formation of MLL core complex and its H3K4 methyltransferase activity. Disrupting MLL1-WDR5 interaction has been proposed as a potential therapeutic approach in the treatment of leukemia. A “toolkit” of well-characterized chemical probe will allow exploring animal studies. Based on a specific MLL1-WDR5 PPI inhibitor (DDO-2117), which was previously reported by our group, we conducted a bioisosterism approach by click chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. We propose 24 as a chemical probe that is suitable for in vivo pharmacodynamic and biological studies of MLL1-WDR5 interaction.
- Chen, Weilin,Chen, Xin,Guo, Xiaoke,Jiang, Zhengyu,Li, Dongdong,Long, Guanlu,Wang, Xianghan,You, Qidong
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- SUBSTITUTED 6-AZABENZIMIDAZOLE COMPOUNDS AS HPK1 INHIBITORS
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The present disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.
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Paragraph 0713; 0826
(2020/05/28)
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- Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5
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MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.
- Li, Dong-Dong,Chen, Wei-Lin,Xu, Xiao-Li,Jiang, Fen,Wang, Lei,Xie, Yi-Yue,Zhang, Xiao-Jin,Guo, Xiao-Ke,You, Qi-Dong,Sun, Hao-Peng
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- High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity
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MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50= 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50= 0.19 μM) in HMT assay.
- Li, Dong-Dong,Chen, Wei-Lin,Wang, Zhi-Hui,Xie, Yi-Yue,Xu, Xiao-Li,Jiang, Zheng-Yu,Zhang, Xiao-Jin,You, Qi-Dong,Guo, Xiao-Ke
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supporting information
p. 480 - 489
(2016/09/13)
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- NOVEL COMPOUNDS
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This invention relates to compounds of formula I their use as inhibitors of the microsomal prostaglandin E2 synthase-1 (mPGES-1), pharmaceutical compositions containing them, and their use as medicaments for the treatment and/or prevention of inflammatory diseases and associated conditions. A, L, M, W, R1, R2, R3, R4, R6, R7, R9, Ra, Rb have meanings given in the description.
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Page/Page column 59
(2012/06/18)
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- Studies on 6-aminoquinolones: Synthesis and antibacterial evaluation of 6-amino-8-methylquinolones
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The 6-aminoquinolone had previously been identified as a new class of quinolone antibacterial agents. To continue our structure-activity relationship (SAR) study in this series, novel 6-amino-8-methylquinolone derivatives have now been synthesized and eva
- Cecchetti, Violetta,Fravolini, Arnaldo,Lorenzini, Maria Cristina,Tabarrini, Oriana,Terni, Patrizia,Xin, Tao
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p. 436 - 445
(2007/10/03)
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