Table 2.

Several types or classes of telomerase inhibitors and their mechanism.

Different Types or Classes of Telomerase Inhibitors	Name of Drugs or Agents	Mechanism of Their Action	Identification Methods	Outcomes and Safety Profile	References
Nucleoside analogs	AZT, stavudine, tenofovir, didanosine and abacavir 6-thio-dG, 5-MeCITP	Incorporate into telomeric DNA to prevents the addition of dNTP and telomerase activity resulting into impairment of telomere except for 6-thio-dG	TRAP method as well as direct telomerase assay were used for validation	Lower efficacy in preclinical cancer models as well as associated with toxicity and nonspecific Less cytotoxic than AZT	[183,184,185,186,187,188]
Modified oligonucleotide	Imetelstat (GRN163L) 13-mer oligonucleotide sequence with thio- phosphoramidate and palmitoyl lipid group	Robustly binds to the human telomerase RNA (hTR) template to hamper its recruitment to telomeric DNA leading telomerase inhibition and shortening of telomeric ends	TRAP method was used for validation	Suppress cellular and tumor growth Limited toxicity in phase I/II clinical trials	[189,190,191,192,193,194,195,196]
Synthetic mixed noncompetitive nonnucleoside inhibitor	BIBR1532 TNQX (2,3,7-trichloro-5-nitroquinoxaline), DPNS (3,5-dichlorophenoxy-nitrostyrene)	Suppress telomerase dependent telomere lengthening	TRAP method was used for validation.	Suppress cellular growth and induce cell death High doses were associated with cytotoxicity	[197,198,199]
Nutraceuticals	MST-312, EGCG, curcumin, quercetin, tannic acid, rhodacyanine, genistein, resveratrol, gambogic acid boldine, gambogenic acid oleanane, berberine, pristimerin	Suppress telomerase activity and telomere shortening	Nutraceuticals and their derivatives were validated via TRAP assay	Reduced tumor growth in a preclinical model Lower stability and bioavailability	[200,201,202,203]
Isothiazolone derivatives	TMPI	Isothiazolone moiety may bind with the sulfhydryl of cysteines in the active site of the TERT to attenuate telomerase enzymatic activity	High-throughput using the TRAP method discovered isothiazolone derivatives including TMPI	No data for effects on cancer cell proliferation	[197,198,199]
G4-DNA stabilizers	CX-5461, BIBR1532, telomestatin, RHPS4, BRACO-19 and TMPyP4, fluorenones, 4-methylpiperidine analog, perylene derivative PIPER, isoalloxazines, quarfloxin naphthalene, TERRA, BBZ-ARO	G-quadruplex has displayed to suppress telomerase activity and telomeric elongation	TRAP method was used for the validation of G-quadruplex stabilizers in blocking the telomere elongation.	Limited stability, pharmacokinetics Bind nonspecifically to g-quadruplex in the promoter and other regions in the genome associated with off-target effects	[204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221] [222,223,224]
HSP90 inhibitors	Geldanamycin, 17-allylaminogeldamycin, novobiocin, radicicol, and alvespimycin	Hamper the assemble of telomerase	Small molecule inhibitors against HSP90 were verified using TRAP assay	Inhibit cellular growth and induce apoptosis of cancer cells	[225,226]

TRAP: telomeric repeat amplification protocol; AZT: azidothymidine; 6-thio-dG: 6-thio-2′-deoxyguanosine; 5-MeCITP: 5-methylcarboxyl-indolyl-2 0 -deoxyriboside 5 0 -triphosphate.; EGCG: Epigallocatechin gallate; TMPI: 2-[3-(trifluoromethyl)phenyl]isothiazolin-3-one; HSP: heat shock protein.