Based on our Fluorescence Linked Enzyme Chemoproteomic Strategy (FLECS), we developed a screening assay in order to find small molecule inhibitors that targets fatty acids synthase (FASN) co-factors binding sites. FASN represents one of the most attractive targets for the treatment of cancer due to that several types of cancer are dependent on de novo fatty acids synthesis which mainly catalyzed by FASN. By screening our library of purine containing small molecules, we were able to identify HS- 106 as a micromolar FASN inhibitor.
HS-106 (later called Fasnall) was able to inhibit fatty acid synthesis activity in several radioactive tracers based assays and was able to inhibit the proliferation and induce apoptosis in several breast cancer cell lines. During the in vivo studies, Fasnall showed bioavailability and was tolerable in mouse models where it did not induce toxicity or weight loss with an i.p dose of 15mg/kg twice weekly. In the MMTV neu mouse model for HER2+ breast cancer, Fasnall was able to double the survival of the mice and when combined with Carboplatin it was able to significantly reduce tumors volume.
Fasnall represents a promising molecule for clinical development and currently is being tested in several cancer mouse models including Patient-Derived Xenografts (PDX) mouse models alone or in combination with Heat shock proteins inhibitor