article · Journal of Medicinal Chemistry
This research focused on modifying the compound BIBR1591 to create new candidates with enhanced activity against telomerase, an enzyme often linked to cancer. The study designed and synthesised novel chemical series, evaluating their ability to inhibit telomerase. Notably, compound 6f demonstrated superior telomerase inhibition compared to both BIBR1532 and the original BIBR1591. Compounds 8a and 8b also showed promising inhibitory effects. These new compounds were tested against various lung and liver cancer cell lines. Further investigations included assessing compound 6f's impact on cell cycle progression, apoptosis induction in cancer cells, and its anti-tumour activity in mice. Molecular docking and dynamics simulations were also performed.
Telomerase is an enzyme that helps cancer cells grow and divide indefinitely. Inhibiting telomerase can therefore be a strategy to stop cancer progression. This research identifies new compounds with improved telomerase inhibitory activity, offering potential avenues for developing more effective cancer treatments.
This research is at an early stage, focusing on the discovery and preclinical assessment of novel telomerase inhibitors. The findings could contribute to the development of new cancer therapeutics. Potential users would be pharmaceutical companies or research organisations interested in oncology drug discovery. The abstract indicates these compounds require further investigation and optimisation before any real-world application.
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Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, <b>6f</b> achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, <b>8a</b> and <b>8b</b> showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. <b>6f</b>, <b>8a</b>, and <b>8b</b> were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, <b>6f</b> was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of <b>6f</b> was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, <b>6f</b>, <b>8a</b>, and <b>8b</b> could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.
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DOI: 10.1021/acs.jmedchem.3c01708
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