A covalent calmodulin inhibitor as a tool to study cellular mechanisms of K-Ras-driven stemness

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Okutachi , S , Manoharan , G B , Kiriazis , A , Laurini , C , Catillon , M , McCormick , F , Yli-Kauhaluoma , J & Abankwa , D 2021 , ' A covalent calmodulin inhibitor as a tool to study cellular mechanisms of K-Ras-driven stemness ' , Frontiers in Cell and Developmental Biology , vol. 9 , 665673 . https://doi.org/10.3389/fcell.2021.665673

Title: A covalent calmodulin inhibitor as a tool to study cellular mechanisms of K-Ras-driven stemness
Author: Okutachi, Sunday; Manoharan, Ganesh Babu; Kiriazis, Alexandros; Laurini, Christina; Catillon, Marie; McCormick, Frank; Yli-Kauhaluoma, Jari; Abankwa, Daniel
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2021-07-08
Language: eng
Number of pages: 17
Belongs to series: Frontiers in Cell and Developmental Biology
ISSN: 2296-634X
URI: http://hdl.handle.net/10138/332864
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 1, here named Calmirasone1, as a novel and potent covalent CaM inhibitor. 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. 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. 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. 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.
Subject: ANTAGONISTS
BINDING
BRET
CANCER
CYTOKINESIS
DESIGN
IDENTIFICATION
K-Ras
OPHIOBOLIN
PHOSPHORYLATION
SUPPRESSION
TARGET
calmodulin
cancer stem cell (CSC)
covalent inhibitor
1182 Biochemistry, cell and molecular biology
317 Pharmacy
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