Our results suggest that Calmirasone1 can serve as a new tool compound to further investigate the cancer cell biology of the K-Ras and CaM associated stemness activities.Ĭalmodulin (CaM) is a small (17 kDa) dumbbell-shaped signaling adapter, with hundreds of protein interactions and widespread functions in cellular signaling ( Tidow and Nissen, 2013). Importantly, Calmirasone1 has a 40–260-fold lower unspecific toxic effect on HRAS mutant cells, while it reaches almost 50% of the activity of novel K-RasG12C specific inhibitors in 3D spheroid assays. Calmirasone1 displayed a 2.5–4.5-fold higher selectivity for KRAS over BRAF mutant 3D spheroid growth than OphA, suggesting improved relative on-target activity. Calmirasone1 has a 4-fold increased affinity for CaM as compared to OphA and was active against K-Ras in cells within minutes, as compared to hours required by OphA. We identified the formyl aminobenzazulenone 1, here named Calmirasone1, as a novel and potent covalent CaM inhibitor. We analyzed a small series of benzazulenones, which bear some structural similarity to OphA and can be synthesized in only six steps. Here we identified a less toxic, functional analog of OphA that can efficiently inactivate CaM by covalent inhibition. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). 4Frederick National Laboratory for Cancer Research, Cancer Research Technology Program, Leidos Biomedical Research, Inc., National Cancer Institute RAS Initiative, Frederick, MD, United States.3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.2Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.1Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.Sunday Okutachi 1, Ganesh Babu Manoharan 1, Alexandros Kiriazis 2, Christina Laurini 1, Marie Catillon 1, Frank McCormick 3,4, Jari Yli-Kauhaluoma 2 and Daniel Abankwa 1*
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