Small Molecules\nBlocking the Assembly of TCAB1 and\nTelomerase Complexes: Lead Discovery and Biological Activity

The vast majority of tumor cells maintain the length\nof the telomeres\nthrough a telomerase-dependent maintenance mechanism, allowing for\nunlimited proliferation. TCAB1 is indispensable for the correct assembly\nof telomerase complexes and the delivery of telomerase to the telomere.\nTherefore, this study aimed to explore small molecules capable of\ninterfering with the assembly of TCAB1 and the telomerase complex\nas novel efficient telomerase inhibitors. Through virtual screening,\nbiological evaluation, and the confirmation of target engagement,\nthe potential ligands of TCAB1 effectively inhibiting telomerase activity\nwere discovered. Among them, compound <b>9</b> exhibited telomerase\ninhibitory activity at a two-digit nanomolar level (IC<sub>50</sub> = 0.03 μM), which was dramatically enhanced in comparison\nwith the previously reported telomerase inhibitors. This research,\nbased on the blockage of telomerase assembly through disturbing TCAB1,\nprovides a novel strategy and a potential target for telomerase inhibitor\ndiscovery.