Abstract 4333: Identification and optimization of the first highly selective GLUT-1 inhibitors

Increased glycolysis rates combined with an insufficient cellular respiration in tumor cells have been known for decades as the Warburg effect (1930). One of the key players in this metabolic alteration of cancer cells is glucose transporter 1 (or GLUT-1), which facilitates the transport of glucose across the plasma membranes of mammalian cells. Many tumor biopsies underline the crucial importance of GLUT-1 overexpression for the vitality of many tumor entities. Moreover the glucose uptake dependency of cancer cells can be visualized by the widespread clinical application of 18fluorodeoxyglucose (FDG) uptake in PET tumor imaging. Therefore, inhibition of glucose uptake for the treatment of cancer seems to be an interesting approach. Based on our first identified GLUT-1 inhibitors (1H-pyrazolo[3,4-d]pyrimidines) with modest selectivity profile, a high throughput screen (HTS) was performed to identify new potent lead structures with unique selectivity against the other members of the GLUT-1 family (GLUT-2,-3 and -4). Among several lead structures we identified from the HTS the quinoline carboxamides with the most promising selectivity profile. Extensive SAR elaboration by synthesizing more than 1600 new derivatives of the lead structure clearly revealed the essential moieties for high activity, potency, and selectivity. Additionally, we were able to improve the in vitro and in vivo PK properties permitting in vivo animal studies. We are able to report for the first time the preclinical profile and structure of the very potent and highly selective GLUT-1 inhibitor BAY-876 representing an ideal tool to further evaluate the scope and limitations of GLUT-1 inhibition as new therapeutic option. Citation Format: Marcus Bauser, Bernd Buchmann, Holger Siebeneicher, Arwed Cleve, Hartmut Rehwinkel, Roland Neuhaus, Iring Heisler, Thomas Mueller, Charlotte Christine Kopitz. Identification and optimization of the first highly selective GLUT-1 inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4333.