6517-69-7Relevant articles and documents
Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction
Aguilar, Angelo,Zheng, Ke,Xu, Tianfeng,Xu, Shilin,Huang, Liyue,Fernandez-Salas, Ester,Liu, Liu,Bernard, Denzil,Harvey, Kaitlin P.,Foster, Caroline,McEachern, Donna,Stuckey, Jeanne,Chinnaswamy, Krishnapriya,Delproposto, James,Kampf, Jeff W.,Wang, Shaomeng
, p. 6015 - 6034 (2019/07/03)
Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
Synthesis and structure-activity relationship of benzetimide derivatives as human CXCR3 antagonists
Bongartz, Jean-Pierre,Buntinx, Mieke,Coesemans, Erwin,Hermans, Bart,Lommen, Guy Van,Wauwe, Jean Van
scheme or table, p. 5819 - 5823 (2009/06/30)
The synthesis and evaluation of benzetimide derivatives showing potent CXCR3 antagonism are described. Optimization of the screening hits led to the identification of more potent CXCR3 antagonists devoid of anti-cholinergic activity and identification of the key pharmacophore moieties of the series.
THE SYNTHESIS OF 1-PHENYL-3,8-DIAZASPIRODECANES
Parys, Marc Van,Vandewalle, Maurits
, p. 757 - 766 (2007/10/02)
The synthesis of some substituted 3,8-diazaspirodecanes is described.Two routes starting from 1-benzyl-4-oxo-piperidine have been explored.The title compounds are isosteric to the 1,3,8-triazaspirodecane structure present in important neuroleptic agents.
