Targeting Telomerase Cajal Body Protein 1 (TCAB1) as a Novel Strategy for Discovering Potent Telomerase Inhibitors That Enhance Antitumor Immunity.

Telomerase, responsible for extending telomeres and maintaining the malignant potential of tumors, has long been deemed a promising anticancer target. Nonetheless, because of its complex composition, the discovery of highly efficient telomerase inhibitors is a challenging task. Herein, we identify the blockage of telomerase assembly via targeting TCAB1 as a novel avenue for potent telomerase inhibition. Upon this strategy, (R)-(3,4-dimethoxyphenyl)(3-(3-hydroxypyrrolidin-1-yl)phenyl)methanone (R)-1b (IC50 = 2.04 nM), which directly targets TCAB1 and impairs telomerase assembly via obstructing the TCAB1-hTR interaction, has been discovered. Notably, its binding pocket and the critical residues are confirmed for further drug design. In vivo, (R)-1b remarkably sensitized tumors to small-molecule PD-L1 inhibitors and induced tumor regression, underscoring its potential for augmenting the efficacy of tumor immunotherapy. This study paves the way for the exploration of telomerase inhibitors with a distinctive mechanism of action via targeting TCAB1 and blocking telomerase assembly.