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Ligand 12459, a potent G‐quadruplex‐interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+α,+β) transcript and an over‐expression of the inactive –β transcript. Spliced intron 6 forming the –β hTERT transcript contained several tracks of G‐rich sequences able to form G‐quadruplexes. By using a specific PCR‐stop assay, we show that 12459 is able to stabilize the formation of these G‐quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the …