Small Molecules Blocking the Assembly of TCAB1 and Telomerase Complexes: Lead Discovery and Biological Activity

The vast majority of tumor cells maintain the length of the telomeres through a telomerase-dependent maintenance mechanism, allowing for unlimited proliferation. TCAB1 is indispensable for the correct assembly of Telomerase complexes and the delivery of Telomerase to the telomere. Therefore, this study aimed to explore small molecules capable of interfering with the assembly of TCAB1 and the Telomerase complex as novel efficient Telomerase inhibitors. Through virtual screening, biological evaluation, and the confirmation of target engagement, the potential ligands of TCAB1 effectively inhibiting Telomerase activity were discovered. Among them, compound 9 exhibited Telomerase inhibitory activity at a two-digit nanomolar level (IC₅₀ = 0.03 μM), which was dramatically enhanced in comparison with the previously reported Telomerase inhibitors. This research, based on the blockage of Telomerase assembly through disturbing TCAB1, provides a novel strategy and a potential target for Telomerase Inhibitor discovery.