Delving into the Latest Updates on AstraZeneca R&D Boston, Inc. with Synapse

作者: Throner, Scott ; Wu, Jiaquan ; Larsen, Nicholas A. ; Russell, Daniel ; Dakin, Leslie A. ; Howard, Tina ; Molina, Audrey ; Pendleton, Christopher S. ; Garcia-Arenas, Renee ; Pietenpol, Jennifer A. ; Ferguson, Andrew D. ; Chen, Huawei ; Godin, Robert ; Cheung, Tony ; Zheng, Xiaolan ; Cowen, Scott D. ; Keen, Nicholas

Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.

2015-06-01·Tetrahedron Letters

From fragments to leads: novel bacterial NAD + -dependent DNA ligase inhibitors

作者: Oguto, Herbert ; Howard, Tina ; Carcanague, Dan ; Hale, Michael R. ; Murphy-Benenato, Kerry E. ; Kutschke, Amy ; Loch, James ; Shapiro, Adam B. ; Embrey, Kevin ; Gingipalli, Lakshmaiah ; Harang, Jenna ; Boriack-Sjodin, P. Ann ; Laganas, Valerie A. ; Ioannidis, Georgine ; Brassington, Claire ; Miller, Matthew D. ; Otterbein, Ludovic ; Giacobbe, Robert A. ; Eyermann, Charles J. ; Patel, Sahil Joe ; Jahic, Haris ; Gowravaram, Madhusudhan

Bacterial NAD⁺-dependent DNA ligase (LigA) is an essential enzyme involved in the repair, replication, and recombination of DNA in all bacteria, making it an attractive target in antibacterial drug discovery.A novel series of LigA inhibitors was discovered by combining information from fragment-based lead generation, X-ray crystal structures of previously discovered inhibitors bound to the adenosine binding site of LigA bound to and established structure-activity relationships of LigA inhibitors.The compounds described here were evaluated in a variety of Gram-pos. and Gram-neg. pathogens as well as evaluation of phys. properties.

2015-04-13·Angewandte Chemie International Edition1区 · 化学

Target‐Based Whole‐Cell Screening by ¹H NMR Spectroscopy

1区 · 化学

Article

作者: Cao, Qing ; McLeod, Sarah M. ; Ferguson, Keith ; Hu, Jun ; Breeze, Alexander L. ; Ma, Junhe ; Gao, Ning

AbstractAn NMR‐based approach marries the two traditional screening technologies (phenotypic and target‐based screening) to find compounds inhibiting a specific enzymatic reaction in bacterial cells. Building on a previous study in which it was demonstrated that hydrolytic decomposition of meropenem in living Escherichia coli cells carrying New Delhi metallo‐β‐lactamase subclass 1 (NDM‐1) can be monitored in real time by NMR spectroscopy, we designed a cell‐based NMR screening platform. A strong NDM‐1 inhibitor was identified with cellular IC50 of 0.51 μM, which is over 300‐fold more potent than captopril, a known NDM‐1 inhibitor. This new screening approach has great potential to be applied to targets in other cell types, such as mammalian cells, and to targets that are only stable or functionally competent in the cellular environment.

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