AUTHOR=Okutachi Sunday , Manoharan Ganesh Babu , Kiriazis Alexandros , Laurini Christina , Catillon Marie , McCormick Frank , Yli-Kauhaluoma Jari , Abankwa Daniel TITLE=A Covalent Calmodulin Inhibitor as a Tool to Study Cellular Mechanisms of K-Ras-Driven Stemness JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.665673 DOI=10.3389/fcell.2021.665673 ISSN=2296-634X ABSTRACT=
Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. Here we identified a less toxic, functional analog of OphA that can efficiently inactivate CaM by covalent inhibition. We analyzed a small series of benzazulenones, which bear some structural similarity to OphA and can be synthesized in only six steps. We identified the formyl aminobenzazulenone