Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera

Expression of telomerase reverse transcriptase (TERT) is a hallmark of cancer, maintaining telomere integrity to enable replicative immortality. However, TERT also serves multiple enzyme-dependent and -independent functions to support cancer growth and survival, including enhanced DNA damage response. Agents that inhibit TERT reverse transcriptase activity prevent telomere elongation but may fail to limit other TERT functions that mediate cancer therapy resistance. Thus, we applied structure-based design, modular synthesis, and biochemical assays towards developing a proteolysis targeting chimera (PROTAC) to drive proteasomal degradation of TERT in cancer cells. This yielded NU-PRO-1, a PROTAC linking the TERT active site-targeted covalent inhibitor NU-1 to the VHL E3-ligase ligand (S,R,S)-AHPC. Applied to cancer cells, NU-PRO-1 induced transient VHL- and proteasome-dependent TERT degradation. NU-PRO-1 did not induce DNA damage on its own but acted to further delay DNA repair after irradiation compared to NU-1. TERT-degrading PROTACs provide novel chemical probes of TERT's non-catalytic functions and may overcome the limitations of current telomerase inhibitors as cancer therapeutics.