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实验室

11:00-12:00, Tuesday, July 3, 2018


Speaker: Jonathan Baell, Ph.D.

Professor of Medicinal Chemistry,

Monash Institute of Pharmaceutical Sciences (MIPS), Monash University

Topic: Histone acetyltransferase inhibitors, from screening to optimization - a tricky track

Host:     Xiangbing Qi ,Ph.D.

Abstract

The first potent, selective, small molecule and AcCoA-competitive inhibitors of MYST histone acetyltransferases with mechanism-based cellular activity. There is currently great interest in compounds that modulate epigenetics. With respect to some epigenetic targets, such as histone decacetylases (HDACs), many inhibitors have been successfully developed and are in clinical trials for a variety of indications. Similarly, bromodomains have been shown, somewhat unexpectedly by some, to be highly druggable. However, there is an elephant in the room, and that is the histone acetyltransferase (HAT) family, which is large but essentially “undrugged” and barely has any compounds that could be considered to be useful tools. Why is it so hard to find good tool compounds for these enzymes? Not so long ago we undertook HTS against a MYST HAT and eventually discovered a genuine hit1 that we have recently just optimized to nanomolar levels of inhibition. However, we encountered many problems en route. In this talk we will discuss such issues and how these could help explain why there are so few, if any, useful tool compounds for these enzymes.


1 H. Falk, T. Connor, H. Yang H, K.J. Loft, J. L. Alcindor, G. E. Nikolakopoulos, R. N. Surjadi, J. D. Bentley, M. K. Hattarki, O. Dolezal, J.M. Murphy, B. J. Monahan, T. S. Peat, T. Thomas, J. B. Baell, J. P. Parisot, I. P. Street, An efficient high-throughput screening method for MYST family acetyltransferases, a new class of epigenetic drug targets J. Biomol. Screening 2011, 16, 1196-1205


Brief Biography of Lecturer: Prof. Jonathan Baell, Ph.D is a Larkins Fellow, Director of the Australian Translational Medicinal Chemistry Facility and an NHMRC Principal Research Fellow, at Monash Institute of Pharmaceutical Sciences (MIPS). He obtained his PhD in 1992 under Professors Peter Andrews and Paul Alewood. Then he obtained a senior position in Australia’s prestigious National Scientific Organisation, CSIRO, where later at the age of 28 he became CSIRO’s youngest Senior Research Scientist. After a decade as Head of Medicinal Chemistry at Australia’s Premier Medical Research Institute, WEHI, he was appointed as a research professor at MIPS, which in 2017 and 2018 was ranked #2 in the world for Pharmacy and Pharmacology (QS World University Rankings). His interests are in the design of quality of HTS libraries, medicinal chemistry hit-to-lead and lead optimization, and computer-aided peptidomimetic design in order to generate compounds with potential therapeutic utility and of value. He has papers in Nature, Nature Communications, Nature Chemical Biology and Journal of Medicinal Chemistry (15) and over 40 granted pharmaceutical patents making key contributions to a number of compounds in various stages of development, from preclinical to one currently in phase I clinical trials for anxiolysis, and has consulted widely for the Australian Biotechnology Industry. In 2005 he was awarded the 2004 Biota Medal, a National Award for Excellence in Medicinal Chemistry for an early to mid-career researcher. His 2010 HTS publication on Pan Assay Interference Compounds, or PAINS, and has been most highly cited primary research article in the Journal of Medicinal Chemistry over a 3-year period, currently tracking at more than 1000 citations. He sits on numerous scientific and editorial advisory boards, including Journal of Medicinal Chemistry, and is Senior Editor of Future Medicinal Chemistry.