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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.

2015-03-12·Journal of Medicinal Chemistry1区 · 医学

Discovery of Efficacious Pseudomonas aeruginosa-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-mechanistic Pharmacokinetic/Pharmacodynamic Model

1区 · 医学

Article

作者: Rooney, Michael ; Tsai, Andy S. ; Bhagunde, Pratik R. ; Sha, Li ; Manjunatha, M. R. ; Quiroga, Olga ; Hatoum-Mokdad, Holia ; Zhao, Shannon X. ; Manyak, Erika L. ; Tan, Beesan ; Harris, Jennifer J. ; Murphy-Benenato, Kerry E. ; Chen, April ; Durand-Reville, Thomas F. ; Uria-Nickelsen, Maria ; Sylvester, Mark ; Ehmann, David E. ; Kim, Aryun ; Shapiro, Adam B. ; Zambrowski, Mark ; Jahic, Haris ; Galullo, Vincent ; Wu, Ye ; Mueller, John ; Patey, Sara ; Davis, Hajnalka E.

To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.

Challenges in the discovery of new antibacterial agents

作者: Barbachyn, Michael

Bacterial resistance to currently available therapeutic agents continues to grow in scope and magnitude.Nevertheless, there has been a steady decline in the number of new antibacterial agents being approved by the various regulatory agencies.Some of the factors behind this unfortunate situation will be briefly discussed.The principal focus will be on challenges associated with finding novel antibacterial agents, especially those effective against Gram-neg. bacteria.The unique physicochem. properties of such agents, as well as the multivariate problem associated with reaching targets essential to the bacteria will be discussed.Finally, some thoughts on screening approaches aimed at identifying new antibacterial scaffolds will be shared.

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