Modeling guided synthesis of potential fatty acid synthase inhibitors for the treatment of diffuse large B-cell lymphoma

Although there has been a significant increase in the long-term survival rate of patients with diffuse large B-cell lymphoma (DLBCL), there is still an unmet need for treating those who are not responsive to current therapeutics.1 It is well known that cells are capable of storing excess glucose as triglycerides, through the conversion of citrate to palmitate by fatty acid synthase (FAS). The up-regulation of FAS across all DLBCL cell types makes it an appropriate target for inhibitor design. Cerulenin has been shown to cause apoptosis in DLBCL cells through fatty acid synthase inhibition, but a low IC50 of 1g/mL prevents it from being more widely used. There is a need for more potent inhibitors of FAS for the treatment of DLBCL. Molecular modeling has been shown to be a useful technique for inhibitor design and could be used to develop more potent analogs of cerulenin. While cerulenin has been shown in complex with bacterial FAS, it has never been shown in complex with human FAS since human FAS structures have shown poor resolution (>3Å). A crystal structure for the KS-MAT di-domain of human FAS has been solved, but is only an apo-structure. This project involves modeling guided synthesis of cerulenin derivatives which are capable of inhibiting the human FAS KS domain.