Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928

Rahul Prakash; Dustin W. Goodlett; Sheelu Varghese; Justyna Andrys; Fahidat A. Gbadamosi; Ricardo H. Arriaza; Megha Patel; Purushottam B. Tiwari; Tomasz Borowski; Maksymilian Chruszcz; Linda S. Shimizu; Geeta Upadhyay

doi:10.1016/j.bmc.2023.117171

Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928

Rahul Prakash, Dustin W. Goodlett, Sheelu Varghese, Justyna Andrys, Fahidat A. Gbadamosi, Ricardo H. Arriaza, Megha Patel, Purushottam B. Tiwari, Tomasz Borowski, Maksymilian Chruszcz, Linda S. Shimizu, Geeta Upadhyay

Chemical Separations Group

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1 Scopus citations

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.

Original language	English
Article number	117171
Journal	Bioorganic and Medicinal Chemistry
Volume	79
DOIs	https://doi.org/10.1016/j.bmc.2023.117171
State	Published - Feb 1 2023

Funding

This research has been supported by NIH R01CA227694, R21CA256424 and Uniformed Serviced University Start-Up funds by Vice President of Research office, USUHS to Geeta Upadhyay. NIH R01CA227694 sub-award to Maksymilian Chruszcz and Linda Shimizu. This research was supported in part by PL-Grid Infrastructure. MD simulations were performed at Academic Computer Centre Cyfronet AGH. Experimental SPR sensorgrams were recorded using a Biacore T200 instrument and evaluated using Biacore T200 Evaluation Software version 1.0 available in Biacore Molecular Interaction Shared Resource (BMISR) facility at Georgetown University. BMISR is supported by a NIH grant P30CA51008. T.B. and J.A. acknowledge partial financial support of the project by the statutory research fund of ICSC PAS. Confocal analysis was supported by Bioinstrumentation Core facility at USUHS. Automated column was performed in the lab of Dr. Campbell McInnes, Drug Discovery & Biomedical Sciences (DDBS), College of Pharmacy, UofSC. HPLC was performed in the lab of Dr. Jie Li, Department of Chemistry and Biochemistry, UofSC. This research was supported in part by PL-Grid Infrastructure. MD simulations were performed at Academic Computer Centre Cyfronet AGH. Experimental SPR sensorgrams were recorded using a Biacore T200 instrument and evaluated using Biacore T200 Evaluation Software version 1.0 available in Biacore Molecular Interaction Shared Resource (BMISR) facility at Georgetown University. BMISR is supported by a NIH grant P30CA51008. T.B. and J.A. acknowledge partial financial support of the project by the statutory research fund of ICSC PAS. Confocal analysis was supported by Bioinstrumentation Core facility at USUHS. Automated column was performed in the lab of Dr. Campbell McInnes, Drug Discovery & Biomedical Sciences (DDBS), College of Pharmacy, UofSC. HPLC was performed in the lab of Dr. Jie Li, Department of Chemistry and Biochemistry, UofSC.

Keywords

LY6K
NSC243928
Triple negative breast cancer

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10.1016/j.bmc.2023.117171

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title = "Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928",

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.",

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author = "Rahul Prakash and Goodlett, {Dustin W.} and Sheelu Varghese and Justyna Andrys and Gbadamosi, {Fahidat A.} and Arriaza, {Ricardo H.} and Megha Patel and Tiwari, {Purushottam B.} and Tomasz Borowski and Maksymilian Chruszcz and Shimizu, {Linda S.} and Geeta Upadhyay",

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doi = "10.1016/j.bmc.2023.117171",

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AU - Varghese, Sheelu

AU - Andrys, Justyna

AU - Gbadamosi, Fahidat A.

AU - Arriaza, Ricardo H.

AU - Patel, Megha

AU - Tiwari, Purushottam B.

AU - Borowski, Tomasz

AU - Chruszcz, Maksymilian

AU - Shimizu, Linda S.

AU - Upadhyay, Geeta

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AB - 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.

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Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928

Abstract

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Keywords

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