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This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)trienes (kuz7 and kuz8b) of natural 13β-and epimeric 13α-series against triple-negative MDA-MB-231 breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13β-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13β-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin.

Background: Onxeo has pioneered a radically new approach of anti-cancer treatment to tackle emergence of resistance: the decoy agonist mechanism of action (MoA). Drugs based on this unprecedented MoA hijack and hyper activate therapeutic targets (decoy effect) leading to exhaustion (agonist effect). This breakthrough MoA has already shown, using our lead compound AsiDNA, target engagement and excellent safety profile in humans and importantly lack of resistance in multiple preclinical studies. These exciting results led us to develop a proprietary platform of oligonucleotides (platON) with decoy agonist properties: the new generation product OX401 targeting PARP, a target already validated in oncology.

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