Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: from thienopyrimidine to quinazoline inhibitors

Article Article scientifique Article Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: from thienopyrimidine to quinazoline inhibitors eng 2022-10-28 2022-10-28 author Boudou Cédric 935335 author Mattio Luce 956390 author Koval Alexey 0000-0002-8920-4426 910996 author Soulard Valentin 956599 author Katanaev Vladimir 0000-0002-7909-5617 910192 1045102 10.3389/fphar.2022.1045102 1663-9812 https://www.frontiersin.org/articles/10.3389/fphar.2022.1045102/full <p> The Wnt-pathway has a critical role in development and tissue homeostasis and has attracted increased attention to develop anticancer drugs due to its aberrant activation in many cancers. In this study, we identified a novel small molecule series with a thienopyrimidine scaffold acting as a downstream inhibitor of the β-catenin-dependent Wnt-pathway. This novel chemotype was investigated using Wnt-dependent triple-negative breast cancer (TNBC) cell lines. Structure activity relationship (SAR) exploration led to identification of low micromolar compounds such as 5a , 5d , 5e and a novel series with quinazoline scaffold such as 9d . Further investigation showed translation of activity to inhibit cancer survival of HCC1395 and MDA-MB-468 TNBC cell lines without affecting a non-cancerous breast epithelial cell line MCF10a. This anti-proliferative effect was synergistic to docetaxel treatment. Collectively, we identified novel chemotypes acting as a downstream inhibitor of β-catenin-dependent Wnt-pathway that could expand therapeutic options to manage TNBC. </p> Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 1264 Voies de signalisation oncogéniques 998 Frontiers in pharmacology 13 2dbbf233-08c7-4410-81be-43a28f1b5af8 Article (Published version) Public Article-scientifique-from-unpaywall.pdf 1704161 application/pdf CC BY ff6942eb-c238-4790-8406-f99a72b91af1 Supplemental data Public DataSheet1_Wnt-pathway inhibitors w.PDF 1434232 application/pdf CC BY dbedc70c-c885-4bd9-bf2f-c9ebe3204af9 Supplemental data Public DataSheet2_Wnt-pathway inhibitors w.docx 5756106 application/vnd.openxmlformats-officedocument.wordprocessingml.document CC BY d7e86135-e0f5-4530-a0d7-b70700ecfc79 Supplemental data Public DataSheet3_Wnt-pathway inhibitors w.xlsx 32042 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet CC BY openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: from thienopyrimidine to quinazoline inhibitors	Frontiers in pharmacology			2022	217	238

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Soulard, Valentin