hTERT-Targeted Library

ChemDiv’s Library of hTERT-Targeting Compounds contains 43,379 small molecules.

The human telomerase reverse transcriptase (hTERT) enzyme plays a critical role in disease development, particularly cancer. hTERT is a catalytic subunit of telomerase, an enzyme responsible for maintaining telomere length, thereby enabling cells to avoid senescence and continue dividing. In most normal somatic cells, hTERT expression is repressed, leading to telomere shortening and eventual cell aging and death. However, in a vast majority of cancers, hTERT is reactivated, granting cells the ability to proliferate indefinitely, which is a main sign of cancerogenesis. This re-activation often results from mutations, altered epigenetic regulation, or other oncogenic processes. Consequently, hTERT has become a significant focus in cancer research, both as a potential biomarker for cancer diagnosis and as a target for therapeutic interventions. Its role in telomere maintenance also implicates it in other age-related diseases and disorders, making hTERT a key component in understanding and treating various links in disease development.

Telomerase presents an appealing target for anti-cancer therapeutics due to its role in cellular immortalization and its prevalent expression in human neoplasms. Since most cancer cells depend on telomerase activity for proliferation, therapeutic strategies have been devised to inhibit those proteins. These strategies focus on targeting the active site of telomerase, the expressions of hTERT and hTERC, the stability of the core enzyme, and the telomeric DNA. Successful approaches often combine traditional drugs with telomerase inhibitors. However, a significant limitation of inhibiting telomerase, whether through small molecules or antisense oligonucleotides, is the delay associated with telomere shortening before cellular effects become apparent. As alternatives, immunotherapy and gene therapy have been developed to exploit, rather than counteract, telomerase expression and activity. Several Phase I clinical trials for hTERT-based immunotherapies in patients with breast, prostate, lung, and other cancers have shown promising clinical and immunological results, inducing functional anti-tumor T cell involvement without clinical toxicity. This approach relies on the presence of the catalytic subunit of telomerase, hTERT, to stimulate an immune response targeting cells presenting hTERT peptides. hTERT promoter-driven gene therapy and mutant telomerase RNA (hTR) gene therapy leverage the inherent telomerase activity of cancer cells to drive the expression of pro-apoptotic genes and to incorporate mutated DNA sequences into telomeres, respectively. Additionally, telomestatin, a G-quadruplex binding ligand, may exert anti-proliferative effects independently of telomere shortening. Disrupting the functional expression of hTERT is particularly effective, aligning with evidence that hTERT acts as an antiapoptotic factor in some cancers. Moreover, approaches that stabilize DNA secondary structures can disrupt telomere maintenance through various mechanisms, potentially making them very effective against cancer cells.

Compounds in development aimed at inhibiting hTERT, the reverse transcriptase component of telomerase, include nucleoside analogs and the small molecule BIBR1532. Those targeting the RNA component of telomerase, hTERC, encompass peptide nucleic acids, 2-5A antisense oligonucleotides, and N3'-P5' thio-phosphoramidates. Recently, an oligonucleotide with sequence homology to terminal telomeric DNA, termed 'T-oligo', has demonstrated cytotoxic effects in multiple cancers in both culture and animal models. Operating independently of telomerase function, T-oligo is believed to mimic the DNA-damage response that occurs when the telomere t-loop structure becomes dysfunctional.

In drug discovery, hTERT plays a significant role, particularly in the development of oncology therapeutics. As a crucial component of telomerase, hTERT enables cancer cells to maintain telomere length and evade senescence, leading to uncontrolled proliferation. This unique characteristic of hTERT in cancer cells, compared to its limited expression in normal somatic cells, makes it an attractive target for developing cancer treatments. Drugs that inhibit hTERT activity could effectively suppress tumor growth by preventing the immortalization of cancer cells. Additionally, hTERT's expression levels can serve as valuable biomarkers for cancer diagnosis and prognosis, aiding in the personalization of cancer therapies. Understanding hTERT's role in drug resistance mechanisms is also crucial for designing next-generation anti-cancer drugs that are more effective and less prone to resistance. Overall, targeting hTERT in drug discovery offers the potential for highly selective cancer therapies with low risk of side effects, that gives a way to the development of the prospective drug candidates against cancer.

Currently, hTERT inhibitors are considered to have some key benefits in the treatment of cancer. Primarily, they target the telomerase reverse transcriptase component of telomerase, which is crucial for the uncontrolled proliferation of cancer cells. By inhibiting hTERT, these drugs can limit the ability of cancer cells to maintain telomere length, leading to cellular aging and death, effectively halting tumor growth. This specificity makes hTERT inhibitors particularly promising as they predominantly target cancer cells while sparing normal cells, potentially reducing the toxicity risks commonly associated with chemotherapy. Furthermore, hTERT inhibitors can be used in conjunction with other cancer therapies to enhance overall treatment effectiveness, especially in cancers where hTERT plays a central role in disease progression. Their use also opens avenues for personalized medicine, as the presence and activity of hTERT can serve as a biomarker for certain cancers. Finally, understanding and overcoming hTERT-related drug resistance mechanisms could lead to more effective treatment strategies, offering hope for improved patient outcomes in various cancer types.

Successful approaches often combine traditional anticancer therapeutics with telomerase inhibitors. Although initially promising, strategies that inhibit telomerase using either small molecules or antisense oligonucleotides face a significant limitation: the time lag required for telomere shortening before cellular effects manifest. As alternative approaches, immunotherapy and gene therapy have been developed to exploit, rather than counteract, telomerase expression and/or activity. Several Phase I studies of hTERT-based immunotherapy in patients with breast, prostate, lung, and other cancers have shown encouraging clinical and immunological results. This form of immunotherapy induces functional, anti-tumor T cells in patients without causing clinical toxicity. It relies on the presence of the catalytic subunit of telomerase, hTERT, to stimulate an immune response targeting cells presenting hTERT peptides. hTERT promoter-driven gene therapy and mutant telomerase RNA (hTR) gene therapy utilize the innate telomerase activity of cancer cells to drive the expression of pro-apoptotic genes and synthesize mutated DNA sequences onto telomeres, respectively. Additionally, telomestatin, a G-quadruplex binding ligand, may exert anti-proliferative effects independently of telomere shortening. Disrupting the functional expression of hTERT proves particularly effective, in line with evidence suggesting hTERT as an anti-apoptotic factor in some cancer cells. Furthermore, approaches that stabilize DNA secondary structures can disrupt telomere maintenance through various mechanisms, potentially making them highly effective in anticancer therapy.