There is increased interest in how the alteration of key metabolic processes can enhance tumorigenesis, and in how these changes might be disrupted in anti-cancer therapies. There is ample evidence that asparagine depletion exerts a tumoricidal effect and the enzyme that mediates asparagine biosynthesis, asparagine synthetase (ASNS), has become of increasing interest as a drug target. For example, knockdown of ASNS expression by small-interfering RNAs in androgen-response and castration-resistant prostate cancer lines inhibited their growth in media devoid of asparagine. Similar effects of ASNS knockdown were observed for prostate cancer cells derived from castration- and chemotherapy-resistant patients. Finally, ASNS is a biomarker for ovarian cancer. We have described the first potent inhibitors of human ASNS and this lecture will discuss the results of in silico screening calculations using an optimized model of ASNS complexed to a key reaction intermediate. These docking studies have identified a new structural motif for ASNS inhibitors that should permit the development of compounds with improved cell permeability than those previously reported.

Structure-based discovery of human asparagine synthetase inhibitors

246th National Meeting (2013)

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