article · Journal of Medicinal Chemistry
Telomerase represents a key biological target for oncology therapies, but existing selective inhibitors such as BIBR1532 suffer from unfavourable pharmacokinetic properties. To address these limitations, two novel series of pyridazine-linked analogues were synthesised, incorporating either cyclopenta[b]thiophene or tetrahydro-1-benzothiophene scaffolds. Laboratory testing identified two compounds, designated 8e and 9e, with superior telomerase inhibition profiles. Compound 8e demonstrated potent antitumour effects in cell cultures of MCF-7 breast cancer and A549 lung cancer, where its influence on cell cycle progression and apoptosis was confirmed. In an in vivo solid Ehrlich carcinoma animal model, treatment with 8e led to reductions in both tumour weight and volume that surpassed the performance of the standard chemotherapy drug doxorubicin. Structural modelling, absorption, distribution, metabolism, and excretion profiling, and structure-activity relationship analyses provided further insights into how specific chemical modifications influence telomerase inhibition.
Targeting telomerase is a significant strategy in cancer therapeutics, but drug discovery has been hindered by compounds with poor drug-like properties. Designing effective synthetic alternatives that inhibit telomerase while performing reliably in living models provides new routes to develop treatments for prevalent cancers such as breast and lung carcinomas, potentially offering higher efficacy than certain existing chemotherapeutic options.
This work could enable the development of new small-molecule cancer therapeutics for pharmaceutical developers and clinical oncologists. The research demonstrates early-stage preclinical development, having advanced through laboratory synthesis, in vitro testing on human cancer cell lines, and preliminary in vivo efficacy in an animal tumour model. Further pharmacokinetic optimisation, comprehensive safety profiling, and formal preclinical regulatory trials remain necessary before potential clinical testing or commercial deployment.
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Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[<i>b</i>]thiophene (<b>8a-f</b>) and tetrahydro-1-benzothiophene (<b>9a-f</b>) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, <b>8e</b> and <b>9e</b> exhibited the best inhibition profiles. Moreover, <b>8e</b> showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of <b>8e</b> on the cell cycle and apoptosis were measured. Besides, <b>8e</b> was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.
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DOI: 10.1021/acs.jmedchem.2c01668
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