Abstract 12P
Background
Triple-negative cancer is characterized by a lack of expression of estrogen receptor α (ERα), progesterone receptor, and HER2/neu, which determines certain difficulties in the treatment of this molecular subtype of cancer. The development of drug candidates for triple-negative breast cancer is especially relevant. The work aims to design new type pentaranes (3-hydroxy-17(1-hydroxyalkyl(aryl))-16,17-cycloalkano)-estra-1,3,5(10)-trienes) and to evaluate their biological activity against breast cancer cells.
Methods
The compounds tested were synthesized in ZIOC from commercial reagents using multistage procedures. Docking was performed by AutoDock Vina using a “rigid/flexible” docking approach. MCF-7 and MDA-MB-231 cells are obtained from ATCC. Cell survival was assessed by the MTT test. ERα activity was analyzed by reporter analysis, protein expression was assessed using immunoblotting.
Results
A number of 16,17-cycloalkanoestratriene derivatives with a reduced binding affinity for the estrogen receptor α calculated by molecular docking have been obtained by multistage modification of estrone. The compounds showed weak activity as estrogen receptor alpha agonists on ERα-positive MCF-7 cells. The compounds inhibited the proliferation of triple-negative MDA-MB-231 breast cancer cells with micromolar IC50 values. The pentarane T120S (3-hydroxy-17-(1(S)-hydroxypropyl)-16,17-cyclohexano)-estra-1,3,5(10)-triene) was selected as a hit. Cyclin D1 expression was notably downregulated in MDA-MB-231 cells after treatments with T120S. Analysis of signalling pathways revealed that compound T120S inhibits Slug, a key transcriptional factor in the epithelial-mesenchymal transition.
Conclusions
Novel pentaranes with low estrogenic potency and high activity against triple-negative breast cancer have been obtained. The epithelial-mesenchymal transition is considered a promising target for this class of compounds. The work was supported by RFBR, project 19-03-00246.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Russian Foundation for Basic Research, project 19-03-00246.
Disclosure
All authors have declared no conflicts of interest.