Imetelstat Explained

Width:250
Width2:200
Tradename:Rytelo
Dailymedid:Imetelstat
Routes Of Administration:Intravenous
Atc Prefix:L01
Atc Suffix:XX80
Legal Us:Rx-only
Legal Us Comment:[1]
Index2 Label:as salt
Cas Number:868169-64-6
Cas Number2:1007380-31-5
Pubchem:72941969
Pubchem2:72941968
Drugbank:DB05036
Chemspiderid:34983285
Chemspiderid2:34983286
Unii:F60NE4XB53
Unii2:2AW48LAZ4I
Kegg:D09629
Kegg2:D09630
Chembl:2107856
Chembl2:2108702
Synonyms:GRN163L
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| C = 148 | H = 211 | N = 68 | O = 53 | P = 13 | S = 13| StdInChI = 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| StdInChIKey = LVZYXEALRXBLJZ-ISQYCPACSA-N| StdInChIKey2 = IEVORMRANFJJFR-NMZIRJKDSA-A| 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| density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

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

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.

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. GRN163 is the pharmacological component with telomerase inhibition based on experiments with poly-G oligonucleotides first conducted at the University of Nebraska Medical Center under contract with Lynx Therapeutics.[6] The palmitic acid moiety is conjugated via a phosphothioate linkage to the backbone of the antisense oligonucleotide. Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro. IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines.[7]

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. Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity. Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group. All participants received supportive care, which included red blood cell transfusions.

Society and culture

Legal status

Imetelstat was approved for medical use in the United States in June 2024. The FDA granted the application for imetelstat orphan drug designation.[8] [9]

Names

Imetelstat is the international nonproprietary name.[10]

External links

Notes and References

  1. Web site: Archived copy . 7 June 2024 . 7 June 2024 . https://web.archive.org/web/20240607214400/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217779s000lbl.pdf . live .
  2. Burchett KM, Yan Y, Ouellette MM . Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells . PLOS ONE . 9 . 1 . e85155 . 2014 . 24409321 . 3883701 . 10.1371/journal.pone.0085155 . 2014PLoSO...985155B . free . doi .
  3. Web site: 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 . 7 June 2024 . 7 June 2024 . https://web.archive.org/web/20240607065259/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent . live .
  4. 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 . Geron . Business Wire . 7 June 2024 . 7 June 2024 . 7 June 2024 . https://web.archive.org/web/20240607025144/https://www.businesswire.com/news/home/20240606850162/en/ . live .
  5. Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, Brogi S, Gemma S, Butini S, Campiani G . Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials . Current Topics in Medicinal Chemistry . 20 . 6 . 433–457 . 2020 . 31894749 . 10.2174/1568026620666200102104930 . 209543655 .
  6. Mata JE, Joshi SS, Palen B, Pirruccello SJ, et al. . A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cellsin Vitro and in Vivo . Toxicology and Applied Pharmacology . 144 . 6 . 189–197 . 1997 . 10.1006/taap.1997.8103 . 9169084 . 1997ToxAP.144..189M .
  7. Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL . Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma . Hepatology . 42 . 5 . 1127–36 . November 2005 . 16114043 . 10.1002/hep.20822 . free . doi .
  8. Web site: Imetelstat Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 7 June 2024 . 7 June 2024 . https://web.archive.org/web/20240607214400/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=481315 . live .
  9. Web site: Imetelstat Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 7 June 2024 . 7 June 2024 . https://web.archive.org/web/20240607214402/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=501415 . live .
  10. ((World Health Organization)) . 2010 . International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63 . WHO Drug Information . 24 . 1 . 10665/74530 . free . World Health Organization .

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