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

On, J. L.; Woloschin, V.; Gier, F.; Tu, J.-W.; Bhatia, S.; Lenz, T.; Stühler, K.; Niederacher, D.; Neubauer, H.; Fehm, T.; Kurz, T.; Esser, K.

doi:10.1101/2024.03.02.582899

bioRxiv · 10.1101/2024.03.02.582899

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

On, J. L.·Woloschin, V.·Gier, F.·Tu, J.-W.·Bhatia, S.·Lenz, T.·Stühler, K.·Niederacher, D.·Neubauer, H.·Fehm, T.·Kurz, T.·Esser, K.

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Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/582899v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@89ffd0org.highwire.dtl.DTLVardef@1f9cba2org.highwire.dtl.DTLVardef@a821b3org.highwire.dtl.DTLVardef@3c7b6a_HPS_FORMAT_FIGEXP M_FIG C_FIG 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 -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 IC50 values ranging between 3.7 {micro}M and 6.6 {micro}M. 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.

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On, J. L., Woloschin, V., Gier, F., Tu, J.-W., Bhatia, S., Lenz, T., Stühler, K., Niederacher, D., Neubauer, H., Fehm, T., Kurz, T., Esser, K.. 2024-03-06. Development of a Bipyrimidineamide based α-Helix Mimetic Lead Compound for efficient Targeting of MDM2 in Triple-Negative Breast Cancer. https://doi.org/10.1101/2024.03.02.582899

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