Modelling and phenotypic screening of NAP-6 and 10-Cl-BBQ, AhR ligands displaying selective breast cancer cytotoxicity in vitro

Baker, Jennifer R.; Pollard, Brett L.; Lin, Andrew J. S.; Gilbert, Jayne; Paula, Stefan; Zhu, Xiao; Sakoff, Jennette A.; McCluskey, Adam

Title: Modelling and phenotypic screening of NAP-6 and 10-Cl-BBQ, AhR ligands displaying selective breast cancer cytotoxicity in vitro
Creator: Baker, Jennifer R.; Pollard, Brett L.; Lin, Andrew J. S.; Gilbert, Jayne; Paula, Stefan; Zhu, Xiao; Sakoff, Jennette A.; McCluskey, Adam
Relation: Australia government HDR scholarship
Relation: ChemMedChem Vol. 16, Issue 9, p. 1499-1512
Publisher Link: http://dx.doi.org/10.1002/cmdc.202000721
Publisher: Wiley-VCH
Resource Type: journal article
Date: 2021
Description: To exploit the interaction of the aryl hydrocarbon receptor (AhR) pathway in developing breast-cancer-specific cytotoxic compounds, we examined the breast cancer selectivity and the docking pose of the AhR ligands (Z)-2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (NAP-6; 5) and 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ; 6). While the breast cancer selectivity of 5 in vitro is known, we discuss the SAR around this lead and, by using phenotypic cell-line screening and the MTT assay, show for the first time that 6 also presents with breast cancer selectivity, notably in the triple-negative (TN) receptor breast cancer cell line MDA-MB-468, the ER+ breast cancer cell lines T47D, ZR-75-1 and the HER2+ breast cancer cell line SKBR3 (GI₅₀ values of 0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 times more potent in MDA-MB-468 cells than normal MCF10A breast cells (GI₅₀ of 0.098 vs 5.4 μM) and more than 130 times more potent than in cell lines derived from pancreas, brain and prostate (GI₅₀ of 0.098 vs 10–13 μM). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N-phenyl moiety for biological activity.
Subject: aryl hydrocarbon receptors; breast cancer; momology modelling; molecular dynamics; naphthalimides; SDG 3; Sustainable Development Goals
Identifier: http://hdl.handle.net/1959.13/1439902
Identifier: uon:41065
Identifier: ISSN:1860-7179
Language: eng
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