Ezatiostat
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MedKoo CAT#: 201360

CAS#: 168682-53-9 (free base)

Description: Ezatiostat is a liposomal small-molecule glutathione analog inhibitor of glutathione S-transferase (GST) P1-1 with hematopoiesis-stimulating activity. After intracellular de-esterification, the active form of ezatiostat binds to and inhibits GST P1-1, thereby restoring Jun kinase and MAPK pathway activities and promoting MAPK-mediated cellular proliferation and differentiation pathways. This agent promotes the proliferation and maturation of hematopoietic precursor cells, granulocytes, monocytes, erythrocytes and platelets. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).


Chemical Structure

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Ezatiostat
CAS# 168682-53-9 (free base)

Theoretical Analysis

MedKoo Cat#: 201360
Name: Ezatiostat
CAS#: 168682-53-9 (free base)
Chemical Formula: C27H35N3O6S
Exact Mass: 529.22466
Molecular Weight: 529.6483
Elemental Analysis: C, 61.23; H, 6.66; N, 7.93; O, 18.12; S, 6.05

Price and Availability

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5.0mg USD 150.0 Same day
10.0mg USD 250.0 Same day
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Related CAS #: 168682-53-9 (free base)   286942-97-0 (HCl)    

Synonym: TLK199; TLK-199; TLK 199; Ezatiostat; Brand name: TELINTRA

IUPAC/Chemical Name: (S)-ethyl 2-amino-5-(((R)-3-(benzylthio)-1-(((S)-2-ethoxy-2-oxo-1-phenylethyl)amino)-1-oxopropan-2-yl)amino)-5-oxopentanoate

InChi Key: GWEJFLVSOGNLSS-FIXSFTCYSA-N

InChi Code: InChI=1S/C27H35N3O6S/c1-3-35-26(33)21(28)15-16-23(31)29-22(18-37-17-19-11-7-5-8-12-19)25(32)30-24(27(34)36-4-2)20-13-9-6-10-14-20/h5-14,21-22,24H,3-4,15-18,28H2,1-2H3,(H,29,31)(H,30,32)/t21-,22-,24-/m0/s1

SMILES Code: O=C(OCC)[C@@H](N)CCC(N[C@@H](CSCC1=CC=CC=C1)C(N[C@@H](C2=CC=CC=C2)C(OCC)=O)=O)=O

Appearance: White solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Ezatiostat (TER199, TLK199, Telintra), a tripeptide analog of glutathione, is a peptidomimetic inhibitor of Glutathione S-transferase P1-1 (GSTP1-1).
In vitro activity: The IC50 values were 22 μM for TLK199 in HT29 human colon adenocarcinoma cells line that express high levels of GSTP1-1. Similar IC50 values (26–28 μM) for TLK199 were obtained with other human colon adenocarcinoma cell lines, e.g., SW620, LoVo, and Caco2. TLK199 is easily taken up by the cells, rapidly converted to phenylglycine monoethyl ester TLK236, and then gradually converted to TLK117. TLK199 undergoes deesterification to glutamyl monoethyl ester TLK235 as well, but this metabolite is only produced in very limited quantities (Figs. 1 and 2). Reference: Handb Exp Pharmacol. 2021;264:71-91. https://dx.doi.org/10.1007/164_2020_392
In vivo activity: The absorption, distribution, metabolism, and elimination properties of TLK199 were characterized in rat and dog. The primary metabolites are TLK236 and TLK117. Unchanged TLK199 was not detected in the blood, although the metabolites TLK117 and TLK236 were, indicating that the systemic clearance of the parent compound was both rapid and extensive. TLK199 has a half-life in rodents of <1 min and in monkeys of ~15 min. Reference: Handb Exp Pharmacol. 2021;264:71-91. https://dx.doi.org/10.1007/164_2020_392

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 155.36
Ethanol 15.0 23.3

Preparing Stock Solutions

The following data is based on the product molecular weight 529.6483 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Zhang J, Ye ZW, Janssen-Heininger Y, Townsend DM, Tew KD. Development of Telintra as an Inhibitor of Glutathione S-Transferase P. Handb Exp Pharmacol. 2021;264:71-91. doi: 10.1007/164_2020_392. PMID: 32767141. 2. Ruscoe JE, Rosario LA, Wang T, Gaté L, Arifoglu P, Wolf CR, Henderson CJ, Ronai Z, Tew KD. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther. 2001 Jul;298(1):339-45. PMID: 11408560.
In vivo protocol: 1. Zhang J, Ye ZW, Janssen-Heininger Y, Townsend DM, Tew KD. Development of Telintra as an Inhibitor of Glutathione S-Transferase P. Handb Exp Pharmacol. 2021;264:71-91. doi: 10.1007/164_2020_392. PMID: 32767141. 2. Ruscoe JE, Rosario LA, Wang T, Gaté L, Arifoglu P, Wolf CR, Henderson CJ, Ronai Z, Tew KD. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther. 2001 Jul;298(1):339-45. PMID: 11408560.

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1: Galili N, Tamayo P, Botvinnik OB, Mesirov JP, Brooks MR, Brown G, Raza A. Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome. J Hematol Oncol. 2012 May 6;5:20. doi: 10.1186/1756-8722-5-20. PubMed PMID: 22559819; PubMed Central PMCID: PMC3407785.

2: Raza A, Galili N, Mulford D, Smith SE, Brown GL, Steensma DP, Lyons RM, Boccia R, Sekeres MA, Garcia-Manero G, Mesa RA. Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS). J Hematol Oncol. 2012 Apr 30;5:18. doi: 10.1186/1756-8722-5-18. PubMed PMID: 22546242; PubMed Central PMCID: PMC3416694.

3: Lyons RM, Wilks ST, Young S, Brown GL. Oral ezatiostat HCl (Telintra®, TLK199) and idiopathic chronic neutropenia (ICN): a case report of complete response of a patient with G-CSF resistant ICN following treatment with ezatiostat, a glutathione S-transferase P1-1 (GSTP1-1) inhibitor. J Hematol Oncol. 2011 Nov 2;4:43. doi: 10.1186/1756-8722-4-43. PubMed PMID: 22047626; PubMed Central PMCID: PMC3235963.

4: Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, Mahadevan D, Mulford D, Rarick M, Brown GL, Schaar D, Faderl S, Komrokji RS, List AF, Sekeres M. A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer. 2012 Apr 15;118(8):2138-47. doi: 10.1002/cncr.26469. Epub 2011 Sep 1. PubMed PMID: 21887679.

5: Quddus F, Clima J, Seedham H, Sajjad G, Galili N, Raza A. Oral Ezatiostat HCl (TLK199) and Myelodysplastic syndrome: a case report of sustained hematologic response following an abbreviated exposure. J Hematol Oncol. 2010 Apr 23;3:16. doi: 10.1186/1756-8722-3-16. PubMed PMID: 20416051; PubMed Central PMCID: PMC2873355.

6: Steensma DP. Novel therapies for myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010 Apr;24(2):423-41. doi: 10.1016/j.hoc.2010.02.010. Review. PubMed PMID: 20359635.

7: D'Alò F, Greco M, Criscuolo M, Voso MT. New treatments for myelodysplastic syndromes. Mediterr J Hematol Infect Dis. 2010 Aug 11;2(2):e2010021. doi: 10.4084/MJHID.2010.021. PubMed PMID: 21415972; PubMed Central PMCID: PMC3033133.

8: Raza A, Galili N, Callander N, Ochoa L, Piro L, Emanuel P, Williams S, Burris H 3rd, Faderl S, Estrov Z, Curtin P, Larson RA, Keck JG, Jones M, Meng L, Brown GL. Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome. J Hematol Oncol. 2009 May 13;2:20. doi: 10.1186/1756-8722-2-20. PubMed PMID: 19439093; PubMed Central PMCID: PMC2694211.

9: Raza A, Galili N, Smith S, Godwin J, Lancet J, Melchert M, Jones M, Keck JG, Meng L, Brown GL, List A. Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood. 2009 Jun 25;113(26):6533-40. doi: 10.1182/blood-2009-01-176032. Epub 2009 Apr 27. PubMed PMID: 19398716.



Additional Information

Related CAS#
168682-53-9 (Ezatiostat);
286942-97-0 (Ezatiostat HCl salt)