871657-76-0Relevant academic research and scientific papers
Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction
Xu, Shilin,Aguilar, Angelo,Xu, Tianfeng,Zheng, Ke,Huang, Liyue,Stuckey, Jeanne,Chinnaswamy, Krishnapriya,Bernard, Denzil,Fernández-Salas, Ester,Liu, Liu,Wang, Mi,McEachern, Donna,Przybranowski, Sally,Foster, Caroline,Wang, Shaomeng
, p. 1601 - 1605 (2018)
The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
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.
HETROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Page/Page column 171, (2008/06/13)
Compounds of Formula (I) wherein: R1 is hydroxymethyl; R2 is selected from -C(O)NR4R5, SO2NR4R5, S(O)pR4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R4 is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R5 is hydrogen or (1-4C)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.
