Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline

Elson, Daniel J.; Nguyen, Bach D.; Bernales, Sebastian; Chakravarty, Sarvajit; Jang, Hyo Sang; Korjeff, Nicholas A.; Zhang, Yi; Wilferd, Sierra F.; Castro, David J.; Plaisier, Christopher L.; Finlay, Darren; Oshima, Robert G.; Kolluri, Siva K.

doi:10.1021/acsptsci.2c00253

Cited by 8 publications

(7 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Collectively, analogues that contained substituents on the phenyl ring (4 and 6-9) including our lead (3) or alterations to the imidazole (13) ring presented with low to moderate growth inhibition (Table 1), suggesting that phenyl ring substituents hinder their biological action. This was further exemplified by analogue 5, the simplest BBQ compound that lacked a phenyl ring substituent, but which induced strong growth inhibition (GI 50 0.001 μM) and 3200-fold selectivity in MDA-MB-468 cells compared with normal breast cells, also previously reported (Elson et al, 2023). In contrast, analogues containing moieties in the naphthyl rings maintained (10) or enhanced growth inhibition potency (11).…”

Section: Discussionmentioning

confidence: 72%

“…Our efforts have generated the halogenated aryl hydrocarbon ANI-7 (1; (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile) and the polyaromatic hydrocarbon NAP-6 (2; (Z)-2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione) (Figure 1) as two molecules displaying more than 500-fold selective targeting of certain breast cancer cell lines compared with normal breast cells or other tumour types via activation of the AhR pathway (Gilbert et al, 2017;Gilbert et al, 2020). We have also demonstrated that 10-Cl-BBQ (3; 10-chloro-7H-benzo[de]benzo [4,5]imidazo[2,1a]isoquinolin-7-one) (Figure 1), a known AhR ligand, is up to 150fold selective in targeting certain breast cancer cell lines compared with normal cells or other tumour types (Baker et al, 2021a;Elson et al, 2023). Leveraging this data, we sought to further explore the breast cancer selectivity and activation of the AhR/CYP1/ SULT1A1 axis of a library of substituted BBQ analogues, in cell line models of the disease.…”

Section: Introductionmentioning

confidence: 82%

“…Herein we present a small chemical library of analogues based upon the chemical structure of 10-chloro-7H-benzo[de]benzo [4,5] imidazo[2,1-a]isoquinolin-7-one (3, 10-Cl BBQ), a compound previously identified as activating the AhR pathway and presenting with selective growth inhibition in cells of breast cancer origin (Baker et al, 2021a;Elson et al, 2023). The library included analogues with modifications to the phenyl ring (4-9), imidazole ring (13), and modifications to the naphthyl rings (10-14).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Next-generation of BBQ analogues that selectively target breast cancer

Baker,

Gilbert,

O’Brien

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001–2.1 μM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1–7 μM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 μM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 μM, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor α-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity.

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Next-generation of BBQ analogues that selectively target breast cancer

Baker,

Gilbert,

O’Brien

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

show abstract

“…Viability assays , were performed using CellTiter-Glo assay (Promega, CA, Cat #G7573) as per the manufacturer’s instructions. DAPI stain was used to assess apoptosis. − Colony-forming assays were performed as described previously.…”

Section: Methodsmentioning

confidence: 99%

Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis

Kopparapu,

Löhr,

Pearce

et al. 2024

ACS Pharmacol. Transl. Sci.

Self Cite

View full text Add to dashboard Cite

The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.

show abstract

“…Additionally, constitutive AhR activity has been reported in multiple BC models of humans and rodents, complemented by recurring inflammatory elements. Hence AhR overexpression in TNBC cells presents a tractable therapeutic paradigm . Genome-wide association studies combined with large-scale data obtained through multigene paneling have revealed PALB2, TP53, PTEN, STK11, BRCA1, and BRCA2 as the TNBC high-penetrance (HP) genes.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Chemotherapeutic Role of the Aryl Hydrocarbon Receptor Antagonist Resveratrol against the High-Penetrance Genes of Triple-Negative Breast Cancer

Chatterjee,

Karn,

Emerson. I

et al. 2024

ACS Omega

View full text Add to dashboard Cite

In addition to several other malignancies, the ligand-activated aryl hydrocarbon receptor (AhR) signaling pathway has been found to enhance the risk of triple-negative breast cancer (TNBC). Many natural compounds of pharmaceutical importance are identified as antagonistic exogenous ligands of AhR. The expressional lack of hormone receptors coupled with adverse prognosis leads to the absence of molecular-targeted therapy in TNBC. Hence, discovering low-cost therapeutic alternatives involving the identification of effective biomarkers is an urgent necessity. This study investigates the binding mechanism of resveratrol, a dietary exogenous AhR ligand against the high-penetrance genes in TNBC, viz., PALB2, TP53, PTEN, STK11, BRCA1, and BRCA2. Postpharmacokinetic evaluation, molecular docking revealed the binding energy scores of resveratrol against the six TNBC highpenetrance receptors. The results obtained from docking were confirmed by molecular dynamics simulation including principal component analysis, calculation of total interaction energy, and free-energy landscape computation. PALB2 emerged as a promising therapeutic receptor of resveratrol. Furthermore, the PALB2−resveratrol binding dynamics were evaluated against olaparib, an FDAapproved standardized TNBC inhibitor. Our study reveals comparatively better chemistry of PALB2−resveratrol than PALB2− olaparib. Considering the current surge in the discovery of precision medicine in biomarker-based cancer therapeutics, this study proposes PALB2−resveratrol as a unique drug−receptor combination thus awaiting validation through in vitro studies.

show abstract

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline

Cited by 8 publications

References 93 publications

Next-generation of BBQ analogues that selectively target breast cancer

Next-generation of BBQ analogues that selectively target breast cancer

Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis

Deciphering the Chemotherapeutic Role of the Aryl Hydrocarbon Receptor Antagonist Resveratrol against the High-Penetrance Genes of Triple-Negative Breast Cancer

Contact Info

Product

Resources

About