Preprint Article Version 1 This version is not peer-reviewed

A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling

Merve Yilmaz
,
Sibel Goksen
ORCID logo ,
Ilgen Mender
,
Gunes Esendagli
,
Sefik E. Erdener
,
Alessandra Ahmed
,
Ates K. Tenekeci
,
Larisa L. Birichevskaya
,
Sergei M. Gryaznov
* ,
Jerry W. Shay
* ORCID logo ,
Z.Gunnur Dikmen
*
Version 1 : Received: 28 September 2024 / Approved: 29 September 2024 / Online: 29 September 2024 (11:06:57 CEST)

How to cite: Yilmaz, M.; Goksen, S.; Mender, I.; Esendagli, G.; Erdener, S. E.; Ahmed, A.; Tenekeci, A. K.; Birichevskaya, L. L.; Gryaznov, S. M.; Shay, J. W.; Dikmen, Z. A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling. Preprints 2024, 2024092316. https://doi.org/10.20944/preprints202409.2316.v1 Yilmaz, M.; Goksen, S.; Mender, I.; Esendagli, G.; Erdener, S. E.; Ahmed, A.; Tenekeci, A. K.; Birichevskaya, L. L.; Gryaznov, S. M.; Shay, J. W.; Dikmen, Z. A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling. Preprints 2024, 2024092316. https://doi.org/10.20944/preprints202409.2316.v1

Abstract

Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG combined with the anti-PD1 inhibitor Cemiplimab is under Phase 2 clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the design, synthesis, and evaluation of novel bimodular conjugate molecules combining telomere-targeting nucleoside analogs and phosphatidyl diglyceride groups. Among them, dihexanoyl-phosphatidyl-THIO (diC6-THIO) showed high anticancer activity with sub-µM EC50 values in vitro across various cancer cell lines. In mouse colorectal cancer models, diC6-THIO demonstrated strong anticancer effects alone and in combination with PD1/PD-L1 inhibitors. Administration of this compound resulted in the efficient formation of Telomere dysfunction Induced Foci (TIFs) in vitro, indicating an on-target, telomerase-mediated telomere-modifying mechanism of action for the molecule. Systemic treatment also activated CD4+ and CD8+ T cells while reducing regulatory T cells, indicating immune system enhancement. These findings highlight diC6-THIO as a promising telomere-targeting prodrug with dual effects on telomere modification and immune activation.

Keywords

Cancer; Telomerase; telomere-targeted therapy; 6-thio-dG; phosphatidyl lipid conjugated 6-thio-dG

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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