Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928. (1st February 2023)

• Record Type: Journal Article
• Authors: Prakash, Rahul; Goodlett, Dustin W.; Varghese, Sheelu; Andrys, Justyna; Gbadamosi, Fahidat A.; Arriaza, Ricardo H.; Patel, Megha; Tiwari, Purushottam B.; Borowski, Tomasz; Chruszcz, Maksymilian; Shimizu, Linda S.; Upadhyay, Geeta
• Is Part Of: Bioorganic & medicinal chemistry. Volume 79(2023)
• Publication Date: 2023-02-01
• Subjects: LY6K -- Triple negative breast cancer -- NSC243928; DFT Density Functional Theory -- LY6K Lymphocytes antigen 6 K -- NBD nitrobenz-2-oxa-1, 3-diazole -- SNAr nucleophilic aromatic substitution -- SPR surface plasmon resonance -- TNBC triple negative breast cancer -- NMR nuclear magnetic resonance -- EtOAc ethyl acetate -- IPA isopropyl alcohol -- NMP N-methyl-2-pyrrolidone -- rt room temperature -- DMF dimethylformamide -- DBU 1, 8-Diazabicyclo[5.4.0]undec-7-ene -- aq. aqueous -- conc. concentrated -- HRMS high-resolution mass spectrometry -- ESI electrospray ionization -- DIPEA N, N-diisopropylethylamine -- HPLC high-performance liquid chromatography; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117171
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Small molecule NSC243928 binds with LY6K, a potential target for the treatment of triple-negative breast cancer, and induces cancer cell death with an unclear mechanism. We have developed chemical tools to identify the molecular mechanisms of NSC243928-LY6K interaction. Herein, we report on the development and synthesis of biotinylated and fluorophore-tethered derivatives of NSC243928 guided by docking studies and molecular dynamics. Surface plasmon resonance assay indicates that these derivatives retained a direct binding with LY6K protein. Confocal analysis revealed that nitrobenzoxadiazole (NBD) fluorophore tagged NSC243928 is retained in LY6K expressing cancer cells. These novel modified compounds will be employed in future in vitro and in vivo studies to understand the molecular mechanisms of NSC243928 mediated cancer cell death. These studies will pave the path for developing novel targeted therapeutics and understanding any potential side-effects of these treatments for hard-to-treat cancers such as triple-negative breast cancer or other cancers with high expression of LY6K.