: We report the structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is >30-times more potent than its corresponding reversible inhibitors. Mass spectroscopic 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. Our study demonstrates that irreversible inhibition of menin may represent a promising therapeutic strategy for MLL leukemia.
[NMR paper] Protein-Inhibitor Interaction Studies Using NMR.
Protein-Inhibitor Interaction Studies Using NMR.
Protein-Inhibitor Interaction Studies Using NMR.
Appl NMR Spectrosc. 2015;1:143-181
Authors: Ishima R
Abstract
Solution-state NMR has been widely applied to determine the three-dimensional structure, dynamics, and molecular interactions of proteins. The designs of experiments used in protein NMR differ from those used for small-molecule NMR, primarily because the information available prior to an experiment, such as molecular mass and knowledge of the primary structure, is...
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[NMR paper] Targeting the Endocannabinoid System for Neuroprotection: A (19)F-NMR Study of a Selective FAAH Inhibitor Binding with an Anandamide Carrier Protein, HSA.
Targeting the Endocannabinoid System for Neuroprotection: A (19)F-NMR Study of a Selective FAAH Inhibitor Binding with an Anandamide Carrier Protein, HSA.
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J Pharm Pharmacol (Los Angel). 2013;1(1)
Authors: Zhuang J, Yang DP, Tian X, Nikas SP, Sharma R, Guo JJ, Makriyannis A
Abstract
Fatty acid amide hydrolase (FAAH), the enzyme involved in the inactivation of the...
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02-19-2014 12:07 AM
[NMR paper] Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers.
Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers.
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--media.wiley.com-assets-2250-98-WileyOnlineLibrary-Button_120x27px_FullText.gif Related Articles Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers.
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013 Jan 17;
Authors: Xue S, Qiao J, Pu F, Cameron M, Yang JJ
Abstract
Magnetic...
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02-03-2013 10:19 AM
Design and NMR Studies of Cyclic Peptides Targeting the N-Terminal Domain of the Protein Tyrosine Phosphatase YopH.
Design and NMR Studies of Cyclic Peptides Targeting the N-Terminal Domain of the Protein Tyrosine Phosphatase YopH.
Design and NMR Studies of Cyclic Peptides Targeting the N-Terminal Domain of the Protein Tyrosine Phosphatase YopH.
Chem Biol Drug Des. 2010 Nov 30;
Authors: Leone M, Barile E, Dahl R, Pellecchia M
We report on the design and evaluation of novel cyclic peptides targeting the N-terminal domain of the protein tyrosine phosphatase YopH from Yersinia. Cyclic peptides have been designed based on a short sequence from the protein SKAP-HOM...
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[NMR paper] The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--fr
The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--from the NMR tube to the clinic.
Related Articles The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--from the NMR tube to the clinic.
Biopolymers. 2004;76(4):309-23
Authors: Tsantrizos YS
The virally encoded serine protease NS3/NS4A is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. Until very recently, the...
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[NMR paper] NMR study on the interaction between MHC class I protein and its antigen peptide.
NMR study on the interaction between MHC class I protein and its antigen peptide.
Related Articles NMR study on the interaction between MHC class I protein and its antigen peptide.
Biochem Biophys Res Commun. 2000 Nov 30;278(3):609-13
Authors: Nakagawa M, Chiba-Kamoshida K, Udaka K, Nakanishi H
A major histcompatibility complex (MHC) class I protein H-2K(b) was expressed in a large scale as a fusion protein with thioredoxin and hexahistidine at the N-terminus to analyze the interaction with the antigen peptide SIYRYYGL. NMR spectra of the...
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Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Related Articles Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Bioorg Med Chem Lett. 2010 Sep 15;
Authors: Petros AM, Huth JR, Oost T, Park CM, Ding H, Wang X, Zhang H, Nimmer P, Mendoza R, Sun C, Mack J, Walter K, Dorwin S, Gramling E, Ladror U, Rosenberg SH, Elmore SW, Fesik SW, Hajduk PJ
The Bcl-2 family of proteins plays a major role in the regulation of apoptosis, or programmed cell death. Overexpression of the anti-apoptotic members of this...
Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction
Linear Mode
