Imetelstat

Medication

US DailyMed: Imetelstat

ATC code

L01XX80 (WHO)

Legal statusLegal status

US: ℞-only^[1]

Identifiers

IUPAC name

N-[2-[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-amino-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(4-amino-2-oxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]oxy-2-hydroxy-ethyl]heptadecanamide

CAS Number

868169-64-6
as salt: 1007380-31-5

PubChem CID

72941969
as salt: 72941968

DrugBank

DB05036

ChemSpider

34983285
as salt: 34983286

UNII

F60NE4XB53
as salt: 2AW48LAZ4I

KEGG

D09629
as salt: D09630

ChEMBL

ChEMBL2107856
as salt: ChEMBL2108702

Chemical and physical dataFormulaC₁₄₈H₂₁₁N₆₈O₅₃P₁₃S₁₃Molar mass4610.18 g·mol⁻¹3D model (JSmol)

Interactive image

SMILES

CCCCCCCCCCCCCCCC(=O)NCC(COP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N2C=C(C(=O)NC2=O)C)NP(=S)(O)OC[C@@H]3[C@H](C[C@@H](O3)N4C=NC5=C(N=CN=C54)N)NP(=S)(O)OC[C@@H]6[C@H](C[C@@H](O6)N7C=NC8=C7N=C(NC8=O)N)NP(=S)(O)OC[C@@H]9[C@H](C[C@@H](O9)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=C(C(=O)NC1=O)C)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=C(C(=O)NC1=O)C)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=CC(=NC1=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)N)S)O

InChI

InChI=1S/C148H211N68O53P13S13/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-97(218)160-34-69(217)38-255-282(242,295)256-51-95-74(25-102(261-95)207-37-68(4)136(221)191-148(207)229)195-274(234,287)249-45-89-78(29-106(264-89)212-61-175-115-124(155)165-56-170-129(115)212)199-277(237,290)252-48-92-81(32-109(267-92)215-64-178-118-132(215)183-143(158)187-139(118)224)202-280(240,293)254-50-94-82(33-110(269-94)216-65-179-119-133(216)184-144(159)188-140(119)225)203-281(241,294)253-49-93-79(30-107(268-93)213-62-176-116-130(213)181-141(156)185-137(116)222)200-278(238,291)246-42-86-72(23-100(260-86)205-35-66(2)134(219)189-146(205)227)193-272(232,285)245-41-85-73(24-101(259-85)206-36-67(3)135(220)190-147(206)228)194-273(233,286)248-44-88-77(28-105(263-88)211-60-174-114-123(154)164-55-169-128(114)211)198-276(236,289)251-47-91-80(31-108(266-91)214-63-177-117-131(214)182-142(157)186-138(117)223)201-279(239,292)250-46-90-76(27-104(265-90)210-59-173-113-122(153)163-54-168-127(113)210)197-275(235,288)244-40-84-71(22-99(258-84)204-20-19-96(150)180-145(204)226)192-271(231,284)247-43-87-75(26-103(262-87)209-58-172-112-121(152)162-53-167-126(112)209)196-270(230,283)243-39-83-70(149)21-98(257-83)208-57-171-111-120(151)161-52-166-125(111)208/h19-20,35-37,52-65,69-95,98-110,217H,5-18,21-34,38-51,149H2,1-4H3,(H,160,218)(H,242,295)(H2,150,180,226)(H2,151,161,166)(H2,152,162,167)(H2,153,163,168)(H2,154,164,169)(H2,155,165,170)(H,189,219,227)(H,190,220,228)(H,191,221,229)(H2,192,231,284)(H2,193,232,285)(H2,194,233,286)(H2,195,234,287)(H2,196,230,283)(H2,197,235,288)(H2,198,236,289)(H2,199,237,290)(H2,200,238,291)(H2,201,239,292)(H2,202,240,293)(H2,203,241,294)(H3,156,181,185,222)(H3,157,182,186,223)(H3,158,183,187,224)(H3,159,184,188,225)/t69?,70-,71-,72-,73-,74-,75-,76-,77-,78-,79-,80-,81-,82-,83+,84+,85+,86+,87+,88+,89+,90+,91+,92+,93+,94+,95+,98+,99+,100+,101+,102+,103+,104+,105+,106+,107+,108+,109+,110+,270?,271?,272?,273?,274?,275?,276?,277?,278?,279?,280?,281?,282?/m0/s1
Key:LVZYXEALRXBLJZ-ISQYCPACSA-N
Key:IEVORMRANFJJFR-NMZIRJKDSA-A

Imetelstat, sold under the brand name Rytelo, is an anti-cancer medication used for the treatment of myelodysplastic syndromes with transfusion-dependent anemia.^[1] Imetelstat is an oligonucleotide telomerase inhibitor.^[1]^[2]

The most common adverse reactions include decreased platelets, decreased white blood cells, decreased neutrophils, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.^[3]

Imetelstat was approved for medical use in the United States in June 2024.^[3]^[4]

Medical uses

Imetelstat is indicated for the treatment of adults with low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents.^[1]^[3]

History

Imetelstat is the first telomerase inhibitor to enter clinical trials.^[5]

Chemically, imetelstat is a synthetic conjugate consisting of three parts: GRN163, a thio phosphoramide oligonucleotide, and a palmitoyl lipid group.^[5] GRN163 is the pharmacological component with telomerase inhibition.^{[medical citation needed]} The palmitic acid moiety is conjugated via a phosphothioate linkage to the backbone of the antisense oligonucleotide.^{[medical citation needed]} Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro.^{[medical citation needed]} IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines.^[6]

The efficacy of imetelstat was evaluated in IMerge (NCT02598661), a randomized (2:1), double-blind, placebo-controlled multicenter trial in 178 participants with myelodysplastic syndromes.^[3] Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity.^[3] Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group.^[3] All participants received supportive care, which included red blood cell transfusions.^[3]

Society and culture

Legal status

Imetelstat was approved for medical use in the United States in June 2024.^[3] The FDA granted the application for imetelstat orphan drug designation.^[3]^[7]^[8]

Names

Imetelstat is the international nonproprietary name.^[9]

References

^ ^a ^b ^c ^d https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217779s000lbl.pdf
^ Burchett KM, Yan Y, Ouellette MM (2014). "Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells". PLOS ONE. 9 (1): e85155. Bibcode:2014PLoSO...985155B. doi:10.1371/journal.pone.0085155. PMC 3883701. PMID 24409321.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia". U.S. Food and Drug Administration (FDA). 6 June 2024. Archived from the original on 7 June 2024. Retrieved 7 June 2024. This article incorporates text from this source, which is in the public domain.
^ "Geron Announces FDA Approval of Rytelo (imetelstat), a First-in-Class Telomerase Inhibitor, for the Treatment of Adult Patients with Lower-Risk MDS with Transfusion-Dependent Anemia" (Press release). Geron. 7 June 2024. Archived from the original on 7 June 2024. Retrieved 7 June 2024 – via Business Wire.
^ ^a ^b Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, et al. (2020). "Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials". Current Topics in Medicinal Chemistry. 20 (6): 433–457. doi:10.2174/1568026620666200102104930. PMID 31894749. S2CID 209543655.
^ Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, et al. (November 2005). "Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma". Hepatology. 42 (5): 1127–36. doi:10.1002/hep.20822. PMID 16114043.
^ "Imetelstat Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 7 June 2024.
^ "Imetelstat Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 7 June 2024.
^ World Health Organization (2010). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63". WHO Drug Information. 24 (1). hdl:10665/74530.

External links

"Imetelstat (Code C49084)". NCI Thesaurus.
"Imetelstat Sodium (Code C84511)". NCI Thesaurus.</ref>
MeSH 67519562

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs
(M phase)

Block microtubule assembly	Vinca alkaloids (Vinblastine^# Vincristine^# Vindesine Vinflunine^§ Vinorelbine^#)
Block microtubule disassembly	Taxanes (Cabazitaxel Docetaxel^# Larotaxel Ortataxel^† Paclitaxel^# Tesetaxel) Epothilones (Ixabepilone)

DNA replication
inhibitor

DNA precursors/
antimetabolites
(S phase)

Folic acid	Dihydrofolate reductase inhibitor (Aminopterin Methotrexate^# Pemetrexed Pralatrexate) Thymidylate synthase inhibitor (Pemetrexed Raltitrexed)
Purine	Adenosine deaminase inhibitor (Pentostatin) Halogenated/ribonucleotide reductase inhibitors (Cladribine Clofarabine Fludarabine) Nelarabine Thiopurine (Mercaptopurine^# Tioguanine^#)
Pyrimidine	Thymidylate synthase inhibitor (Capecitabine^# Carmofur Doxifluridine Floxuridine Fluorouracil^# Tegafur (+gimeracil/oteracil)) DNA polymerase inhibitor (Cytarabine^# +daunorubicin) Ribonucleotide reductase inhibitor (Gemcitabine^#) Hypomethylating agent (Azacitidine Decitabine)
Deoxyribonucleotide	Ribonucleotide reductase inhibitor (Hydroxycarbamide^#)

Topoisomerase inhibitors
(S phase)

I	Camptotheca (Belotecan Camptothecin Cositecan^† Etirinotecan pegol^† Exatecan Gimatecan Irinotecan^# Lurtotecan^‡ Rubitecan^‡ Silatecan^§ Topotecan)
II	Podophyllum (Etoposide^# Teniposide)
II+Intercalation	Anthracyclines (Aclarubicin Amrubicin^† Daunorubicin^# (+cytarabine) Doxorubicin^# Epirubicin Idarubicin Pirarubicin Valrubicin Zorubicin) Anthracenediones (Losoxantrone Mitoxantrone Pixantrone) Amsacrine Bisantrene Crisnatol Menogaril^§

Crosslinking of DNA
(CCNS)

Alkylating	Nitrogen mustards: Bendamustine^# Chlormethine Cyclophosphamide^# (Ifosfamide^# Trofosfamide) Chlorambucil^# Melphalan (Melphalan flufenamide) Prednimustine Uramustine Nitrosoureas: Carmustine Fotemustine Lomustine (Semustine) Nimustine Ranimustine Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan Treosulfan) Aziridines: Carboquone Thiotepa Triaziquone Triethylenemelamine
Platinum-based	Carboplatin^# Cisplatin^# Dicycloplatin Nedaplatin Oxaliplatin^# Satraplatin
Nonclassical	Altretamine Hydrazines (Procarbazine^#) Etoglucid Mitobronitol Pipobroman Triazenes (Dacarbazine^# Mitozolomide^§ Temozolomide)
Intercalation	Streptomyces (Dactinomycin^# Bleomycin^# Mitomycins Plicamycin)

Photosensitizers/PDT

Other

Enzyme inhibitors	FI (Tipifarnib^§) CDK inhibitors (Abemaciclib Alvocidib^† Palbociclib Ribociclib Seliciclib^†) PrI Bortezomib Carfilzomib Oprozomib Ixazomib PhI (Anagrelide) IMPDI (Tiazofurin^§) LI (Masoprocol) PARP inhibitor (Fuzuloparib) Niraparib +abiraterone acetate Olaparib Rucaparib) HDAC (Belinostat Entinostat Panobinostat Romidepsin Vorinostat) PIKI (Pi3K) (Alpelisib Copanlisib Duvelisib Idelalisib Umbralisib^‡)
Receptor antagonists	ERA (Atrasentan) Retinoid X receptor (Bexarotene) Sex steroid (Testolactone)
Other/ungrouped	Adagrasib Aflibercept Arsenic trioxide Asparagine depleters (Asparaginase^#/Pegaspargase) Axicabtagene ciloleucel Belzutifan Bexarotene Brexucabtagene autoleucel Celecoxib Ciltacabtagene autoleucel Demecolcine Denileukin diftitox Eflornithine Elesclomol^§ Elsamitrucin Enasidenib Epacadostat Eribulin Estramustine Glasdegib Idecabtagene vicleucel Imetelstat Ivosidenib Lifileucel Lonidamine Lucanthone Lurbinectedin Mitoguazone Mitotane Navitoclax Oblimersen^† Omacetaxine mepesuccinate Plitidepsin Retinoids (Alitretinoin Tretinoin^#) Selinexor Sitimagene ceradenovec Sotorasib Tagraxofusp Talimogene laherparepvec Tazemetostat Tebentafusp Tiazofurine Tigilanol tiglate Tisagenlecleucel Trabectedin Veliparib Venetoclax Verdinexor Vosaroxin