The development of therapies for cancer continues to be a major priority in modern day health care. In particular, therapies that focus on new protein targets can provide novel and possibly selective approaches to cancer chemotherapy. The recent finding by the Smith group that certain beta-lactones (2-oxetanones, e.g., Orlistat/R) inhibit the thioesterase (TE) domain of fatty acid synthase (FAS) provides a novel drug lead for cancer treatment as fatty acid metabolism has been linked to tumor onset and progression. Towards this end, the development and application of asymmetric methods for the synthesis of collections of structurally related beta-lactones and derivatives followed by their subsequent biological testing for inhibition of FAS is expected to provide highly potent and selective antagonists. In particular, we propose the development of a combination solution/solid phase strategy for the parallel synthesis of Orlistat derivatives with potential activity as FAS antagonists. Also proposed is a novel in situ ketene generation/dimerization/hydrogenation sequence for the efficient, two-step synthesis of 3,4-disubstituted beta-lactones as potential FAS antagonists. The activity of beta-lactones prepared by these methods will be tested for potency and selectivity in their ability to act as antagonists of FAS and its recombinant thioesterase domain. Following further verification of the activity of these compounds as FAS antagonists in cell-based assays, inhibitors of cellular fatty acid synthesis, proliferation, inducers of apoptosis, and finally selectivity, three to six compounds will be selected for testing in animal models of tumor growth. Based on the structure of Orlistat, we propose hypotheses regarding the interactions of beta-lactone antagonists of FAS that will be tested by analysis of structure-activity relationships of novel beta-lactones to be synthesized. X-ray crystallographic studies to determine the three dimensional structure of FAS in complex with Orlistat/R and congeners will also be undertaken. The long-term objective is to identify compound(s) that can be taken into pre-clinical development (i.e., pharmacokinetic analysis and extensive toxicity testing).
| Zhu, Mingzhao; Harshbarger, Wayne D; Robles, Omar et al. (2017) A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids. Bioorg Med Chem 25:2901-2916 |
| Richardson, Robyn D; Ma, Gil; Oyola, Yatsandra et al. (2008) Synthesis of novel beta-lactone inhibitors of fatty acid synthase. J Med Chem 51:5285-96 |
| Browne, Cecille D; Hindmarsh, Elizabeth J; Smith, Jeffrey W (2006) Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J 20:2027-35 |
