KATching-Up on Small Molecule Modulators of Lysine Acetyltransferases
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- 作者：Roman P. Simon ; Dina Robaa ; Zayan Alhalabi ; Wolfgang Sippl ; Manfred Jung
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 25, 2016
- 年：2016
- 卷：59
- 期：4
- 页码：1249-1270
- 全文大小：808K
- 年卷期：Roman P. Simon
holds a diploma degree in Pharmaceutical Sciences at the Institute of Pharmaceutical Sciences of the Albert-Ludwigs University Freiburg and works as a Ph.D. candidate in the group of Prof. M. Jung. He studied Pharmacy (state examination) at the University of Freiburg from 2008 to 2013. After a six months research stay in the group of Prof. Ganesan at the University of East Anglia in 2014, he returned to Freiburg. Since the beginning of 2015, he is a doctoral student, with his research focusing on development and characterization of novel small molecule KAT inhibitors.Dina Robaa
studied Pharmacy at the University of Alexandria in Egypt. She obtained her Ph.D. in Pharmaceutical Chemistry at the University of Jena in the group of Jochen Lehmann. Since 2011, she has been working as a postdoctoral fellow in the research group of Wolfgang Sippl. Her research focuses on structure-based drug design of several epigenetic modulators.Zayan Alhalabi
studied Pharmacy at the University of Damascus in Syria. She finished her diploma in Pharmaceutical Science. She obtained her master’s degree in Pharmaceutical Chemistry at the University of Damascus 2012. In 2013, she started her Ph.D. at the Department of Medicinal Chemistry in the research group of Prof. Wolfgang Sippl. Her research focuses on structure-based drug design for epigenetic targets (Sirtuins).Wolfgang Sippl
is Professor for Medicinal Chemistry and Director of the Institute of Pharmacy at the Martin-Luther-University of Halle-Wittenberg (Germany). He obtained a Ph.D. in Pharmaceutical Chemistry at the University of Düsseldorf in the group of Hans-Dieter Höltje and was a postdoctoral fellow at the Université Louis-Pasteur in Strasbourg (France) where he worked with Camille G. Wermuth. Since 2003, he is Full Professor at the Institute of Pharmacy in Halle. His main interests are focussed on computational chemistry and structure-based drug design of novel epigenetic modulators for the therapy of cancer and parasitic diseases.Manfred Jung
did his Ph.D. with W. Hanefeld on the synthesis of aromatic retinoids at the University of Marburg. In 1993/94, he did a postdoc with T. Durst (University of Ottawa, Canada). From 1994 to 2003 he was a group leader at the University of Münster and obtained his habilitation in Pharmaceutical Chemistry (2000). Since 2003, he is a Professor of Pharmaceutical Chemistry at the University of Freiburg. In 2010, he declined an offer for a full professorship to the University of Mainz and is a Full Professor in Freiburg since 2011. The topic of his research is Chemical Epigenetics. His group is working on inhibitor synthesis, assay development, and screening for inhibitors of reversible histone acetylation and methylation but also histone readers. - ISSN：1520-4804
文摘
The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiological and pathological processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equilibrium at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clinical trials. Here, we review the evidence for the diverse roles of KATs in disease pathology, provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook.