Modelling and Phenotypic Screening of NAP-6 and 10-Cl-BBQ, AhR Ligands Displaying Selective Breast Cancer Cytotoxicity in Vitro

To exploit the interaction of the aryl hydrocarbon receptor(AhR) pathway in developing breast-cancer-specific cytotoxiccompounds, we examined the breast cancer selectivity and thedocking 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 isknown, we discuss the SAR around this lead and, by usingphenotypic cell-line screening and the MTT assay, show for thefirst time that 6 also presents with breast cancer selectivity,notably in the triple-negative (TN) receptor breast cancer cellline MDA-MB-468, the ER + breast cancer cell lines T47D, ZR-75-1 and the HER2 + breast cancer cell line SKBR3 (GI50 values of0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 timesmore potent in MDA-MB-468 cells than normal MCF10A breastcells (GI50 of 0.098 vs 5.4 μM) and more than 130 times morepotent than in cell lines derived from pancreas, brain andprostate (GI50 of 0.098 vs 10–13 μM). Molecular docking posesof 5 and 6 together with analogue synthesis and phenotypicscreening show the importance of the naphthalene moiety, andan ortho-disposed substituent on the N-phenyl moiety forbiological activity.