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Your search keyword '"Moustakim, M."' showing total 2 results
Start Over Author "Moustakim, M." Topic small molecule libraries
2 results on '"Moustakim, M."'

1. Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Author

Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Díaz-Sáez L, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Brennan PE, and Fedorov O

Subjects
Crystallography, X-Ray, Histones metabolism, Humans, Molecular Docking Simulation, Neoplasm Proteins metabolism, Nuclear Proteins metabolism, Protein Domains, Protein Interaction Maps drug effects, Small Molecule Libraries pharmacology, Transcription Factors metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins chemistry, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins chemistry, Small Molecule Libraries chemistry, Transcription Factors antagonists & inhibitors, Transcription Factors chemistry
Abstract

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2018
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2. Target Identification Using Chemical Probes.

Author

Moustakim M, Felce SL, Zaarour N, Farnie G, McCann FE, and Brennan PE

Subjects
Epigenesis, Genetic drug effects, Humans, Molecular Targeted Therapy methods, Drug Discovery methods, Drug Evaluation, Preclinical methods, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology
Abstract

Chemical probes are small molecules with potency and selectivity for a single or small number of protein targets. A good chemical probe engages its target intracellularly and is accompanied by a chemically similar, but inactive molecule to be used as a negative control in cellular phenotypic screening. The utility of these chemical probes is ultimately governed by how well they are developed and characterized. Chemical probes either as single entities, or in chemical probes sets are being increasingly used to interrogate the biological relevance of a target in a disease model. This chapter lays out the core properties of chemical probes, summarizes the seminal and emerging techniques used to demonstrate robust intracellular target engagement. Translation of target engagement assays to disease-relevant phenotypic assays using primary patient-derived cells and tissues is also reviewed. Two examples of epigenetic chemical probe discovery and utility are presented whereby target engagement pointed to novel disease associations elucidated from poorly understood protein targets. Finally, a number of examples are discussed whereby chemical probe sets, or "chemogenomic libraries" are used to illuminate new target-disease links which may represent future directions for chemical probe utility., (© 2018 Elsevier Inc. All rights reserved.)

Published
2018
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