Development of a Bipyrimidineamide based α-Helix Mimetic Lead Compound for efficient Targeting of MDM2 in Triple-Negative Breast Cancer

Abstract Figure Triple-negative breast cancer (TNBC) represents the most aggressive form among breast carcinoma subtypes. Due to limited therapy options, identification of novel active pharmacological compounds is an urgent medical need. A promising approach in cancer treatment is the pharmacological inhibition of murine double minutes 2 (MDM2)-p53/p73 interactions inducing apoptosis in tumors. We here describe a novel bipyrimidineamide based α-helix mimetic 9 (VWK603) which was designed as a lead candidate to target MDM2. 9 (VWK603) potently induced cell death in the TNBC cell lines MDA-MB-231, MDA-MB-436 and MDA-MB-468 with IC 50 values ranging between 3.7 µM and 6.6 µM. The anti-tumor activity was about four more potent higher than determined for the MDM2-specific inhibitor Nutlin-3a. Mechanistic analysis revealed induction of cellular apoptosis as the underlying mode of action of 9 (VWK603) anti-tumor activity. Since toxicity was observed to be reduced in non-cancerous breast cells, these studies make 9 (VWK603) a promising candidate for further preclinical MDM2 inhibitor development.