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New Opportunities For Covalent Drugs Published By Avila Scientists

April 1, 2011

Avila scientists publish ‘The Resurgence of Covalent Drugs’ in Nature Reviews Drug Discovery; publication recognizes the potential of rational covalent drug design to expand the breadth of therapeutic use of targeted covalent drugs

Avila Therapeuticsâ“¢, Inc., a biotechnology company developing novel targeted covalent drugs, today announced the publication of a scientific review article in Nature Reviews Drug Discovery titled “The Resurgence of Covalent Drugs” (www.nature.com/reviews/drugdisc, Vol. 10, April 2011, Singh, J.). This article discusses the broad opportunities for covalent drugs and how structural bioinformatics coupled with structure-based drug design can enable the design of highly selective covalent drugs with unique therapeutic properties for treating diseases.

“Many important and widely-used medicines work through a covalent mechanism of action,” commented Juswinder Singh, PhD, Avila’s Chief Scientific Officer and lead author on the publication. “Until recently, such covalent drugs were discovered by chance. However, today it is possible to design highly-specific covalent drugs by systematically applying rational drug design techniques and leveraging the vastly greater availability of structural information on disease targets. We anticipate the next few years will see an emergence of innovative covalent drugs that can solve problems that have been challenging for traditional medicinal chemistry approaches.”

The Nature Reviews Drug Discovery article examines the prevalence of covalent drugs, safety considerations, mechanistic and pharmacological features, and approaches to design and optimization of targeted covalent inhibitors. Key points include:

    * Covalent drugs have made a major positive impact on human health, and there are dozens of covalent drugs on the market worldwide including broadly used medicines such as aspirin, clopidogrel (Plavix®), lansoprazole (Prevacid®) and esomeprazole (Nexium®).

    * Despite the many successful covalent drugs, principles for the rational design of these molecules have only recently emerged. A description of progress in the design of targeted covalent drugs with a focus on the Avila strategy is discussed.

    * Several rationally designed, targeted covalent inhibitors have recently advanced in clinical development (neratinib, afatinib, PCI-32765 and the Avlia clinical candidate, AVL-292).

    * New publications have reported on targeted covalent inhibitors to diverse drug targets where each demonstrates high specificity of covalent bond formation to its respective target.

    * The pharmacological advantages of covalent drugs are discussed including the potential to address the problem of drug-resistance mutations that often arise in cancer and in infectious diseases.

Based on this review article, it is apparent that structural bioinformatics approaches, coupled with structure-based drug design, may enable the engineering of highly selective covalent drugs and a resurgence of interest in this important class of therapeutics.

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