173315-54-3Relevant academic research and scientific papers
Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity
Chen, Weilin,Chen, Xin,Guo, Xiaoke,Jiang, Zhengyu,Li, Dongdong,Long, Guanlu,Wang, Xianghan,You, Qidong
, (2021/07/06)
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.
Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5
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
, p. 1 - 8 (2016/05/10)
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.
5,6,7,8-TETRAHYDRO[1,2,4]TRIAZOLO[4,3-a]PYRAZINE DERIVATIVES AS P2X7 MODULATORS
-
Page/Page column 98-99, (2010/11/17)
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein A is hydrogen, C1-4alkyl, C3-6cycloalkyl, C1-3alkoxy, C1-3alkoxy C1-4alkyl, C1-2fluoroalkyl, halogen, NR6 R7, optionally substituted heteroaryl (Het), or optionally substituted phenyl, and R1, R2, R3, R4, R5, R6 and R7 are as defined in the description. The compounds or salts are thought to modulate P2X7 receptor function and to be capable of antagonizing the effects of ATP at the P2X7 receptor. The invention also provides the use of the compound or salt in the treatment or prophylaxis of, for example, inflammatory pain, neuropathic pain, visceral pain, rheumatoid arthritis, osteoarthritis or neurodegenerative disorders.
Studies on 6-aminoquinolones: Synthesis and antibacterial evaluation of 6-amino-8-methylquinolones
Cecchetti, Violetta,Fravolini, Arnaldo,Lorenzini, Maria Cristina,Tabarrini, Oriana,Terni, Patrizia,Xin, Tao
, p. 436 - 445 (2007/10/03)
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
