Thymogen Research, Specifications & Scientific Information

Thymogen is the dipeptide L-alpha-glutamyl-L-tryptophan, isolated by chromatography from a calf thymus peptide complex and then synthesised. It is the only compound in the Khavinson bioregulator series with an International Nonproprietary Name and a registered clinical trial record, both of which belong to its disodium salt under the development code IM-862. It is not approved by the FDA for any indication.

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Category: Peptide bioregulators

Introduction

Thymogen is the exception in its family, and the reason is a second name.

The molecule is a dipeptide — glutamic acid joined to tryptophan, 333 daltons — isolated by reversed-phase chromatography from the calf thymus peptide complex Thymalin and then made by synthesis [1]. Under that name it belongs to the Khavinson bioregulator series and shares that series' evidence problems. But the same molecule, as its disodium salt, acquired an International Nonproprietary Name — oglufanide — and a development code, IM-862, and under that code it went through registered clinical trials in the United States in oncology, with a published randomised study and three records on ClinicalTrials.gov. No other compound in this batch has that.

The shared limitations of the bioregulator literature still apply to everything written about this molecule under its trade name: a single originating institute in St Petersburg, much of the output in Russian-language journals, small and often unstated group sizes, an emphasis on cell and organotypic culture, and little independent replication. What is unusual here is that a separate, independent, Western clinical programme examined the same substance — and its results are on the record, including the part where the development stopped.

What Is Thymogen?

A dipeptide with an alpha-peptide bond: L-alpha-glutamyl-L-tryptophan, EW in single-letter code.

The 1997 account from the originating group describes the chain of derivation plainly. Natural thymic peptides were obtained from calf thymus by mild acid extraction and the resulting preparation entered practice as an immunocorrector. One immunomodulatory molecule was then isolated from that complex by reversed-phase HPLC, and a preparation containing the synthesised dipeptide was designed around it. In the same paper a further dipeptide, Vilon, is described as newly synthesised rather than isolated [1].

Three naming facts are worth holding separately, because collapsing them is the commonest error about this compound.

  • Thymogen and Timogen are trade names for the free dipeptide, which PubChem carries as compound identifier 100094 alongside the name oglufanide.
  • Oglufanide disodium is the disodium salt — a different record, compound identifier 158780, CAS registry number 237068-57-4 — and a different substance in a specification sense, though the same molecule in solution.
  • IM-862 is the development code under which that salt was investigated in oncology.

Neither form has been approved by the U.S. Food and Drug Administration for any indication.

Thymogen Specifications

Compound name
Thymogen
Full chemical name
L-alpha-glutamyl-L-tryptophan
Aliases
Glu-Trp, EW peptide, oglufanide, Timogen, alpha-Glu-Trp, glutamyl-tryptophan
Development code
IM-862 (as the disodium salt, oglufanide disodium)
CAS number
38101-59-6
PubChem CID
100094
UNII
4RHY598T5U
Compound type
Synthetic dipeptide
Peptide family
Khavinson peptide bioregulators — short synthetic peptides derived from tissue-specific polypeptide extracts; the only member of the series carrying an International Nonproprietary Name
Amino acid sequence
EW
Sequence length
2 residues
Molecular formula
C16H19N3O5
Molecular weight
333.34 g/mol
Primary target
Not publicly characterised
Secondary targets
Not publicly characterised
Receptor family
Not publicly characterised
Agonist / antagonist status
Not publicly characterised

Two register records exist and the distinction between them is load-bearing. The free dipeptide is PubChem compound identifier 100094, CAS registry number 38101-59-6, FDA/NCATS unique ingredient identifier 4RHY598T5U, formula C16H19N3O5, average mass 333.34 g/mol; it carries the International Nonproprietary Name oglufanide and the trade name Thymogen. The disodium salt is a separate record — PubChem compound identifier 158780, CAS registry number 237068-57-4, unique ingredient identifier Q60AU1LLNU, formula C16H17N3Na2O5, average mass 377.30 g/mol — named oglufanide disodium and assigned the development code IM-862. Every registered clinical trial identified for this molecule used the disodium salt under that code, while almost all of the gerontology literature uses the free dipeptide under the trade name. The bond is an alpha-peptide bond from the glutamate alpha-carboxyl; a gamma-linked isomer of the same two residues exists, is a different substance, and has been reported to behave differently in the same assay.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does Thymogen Work?

Two mechanistic accounts exist for this molecule and they have never been reconciled with one another.

The immunological account comes from the originating group and is the older of the two. It describes activation of T-cell differentiation and of T-cell recognition of peptide–MHC complexes, changes in the intracellular composition of cyclic nucleotides, altered interleukin-2 and interferon output from blood lymphocytes, and activation of neutrophil chemotaxis and phagocytosis [1]. That is a list of observed effects at the level of cells and cytokines. It is not a mechanism, and the paper does not name a receptor.

The antiangiogenic account comes from the oncology programme. The published Kaposi's sarcoma study describes the compound simply as a naturally occurring peptide with antiangiogenic properties, and proceeds to a clinical endpoint without identifying a molecular target [3]. A rationale strong enough to carry a molecule into Phase 2 in the United States would normally be supported by a named pathway somewhere in the public record; for this compound that support has not been located.

Stereochemistry constrains both accounts. Work on the optical and chemical isomers of this dipeptide reports that the all-L forms had no effect on proliferation of committed and pluripotent spleen colony-forming units in intact bone marrow, while inverting the optical form of the glutamate residue conferred suppressor properties, and that changing the peptide bond from alpha to gamma changed the result again [8, 9]. A molecule whose activity flips with a single stereocentre is interacting with something chiral and specific. That is an argument for a discrete binding partner existing — and it is also a reminder that a certificate of analysis which does not establish stereochemistry has not established the substance.

No pharmacokinetic dataset for either form has been located. The clinical programme administered the salt as intranasal drops, which is itself an implicit statement about the other routes.

Human Research on Thymogen

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

All identified human work used the disodium salt under the code IM-862, not the free dipeptide under its trade name.

Design. Forty-two men and two women with AIDS-related Kaposi's sarcoma, median age 38 years, were randomised between two intranasal schedules of 5 mg: five days on followed by five days off (18 participants), or every other day (26 participants), in repeated cycles until progression or unacceptable toxicity. Three-quarters had received prior systemic chemotherapy; 55% had CD4-positive lymphocyte counts at or below 200/mm³; all but five were on concurrent protease inhibitors [3].

Results as reported. Major responses in 36% — five complete and eleven partial remissions — occurring after a median of 6 weeks and lasting a median of 33 or more weeks. Twenty-one participants had stable disease for 7 to 72 or more weeks. Adverse effects were limited to mild and transient headache, fatigue, tingling and nausea, with no haematological toxicity attributed to the compound [3].

What the design supports and what it does not. The randomisation was between two schedules of the same compound, not against placebo or an active comparator, so the 36% response proportion has no control arm behind it. The paper says so itself, closing with the note that a randomised double-blinded study was then in progress. No such study has been located in the published record.

Registered oncology trials

Three records exist on ClinicalTrials.gov, and their status is as much of the evidence as their design.

  • A Phase 1 study of escalating amounts in recurrent ovarian cancer, sponsored by the University of Southern California, 43 participants, begun February 1999 and completed August 2001 [4].
  • A Phase 2 randomised placebo-controlled double-blind study with fluorouracil or irinotecan in metastatic colorectal cancer, 18 participants, begun November 1999 and terminated in November 2001 [5].
  • A Phase 2 study with paclitaxel and carboplatin in newly diagnosed advanced epithelial ovarian or primary peritoneal carcinoma followed by consolidation, sponsored by Cytran, begun January 2001, record status unknown [6].

Eighteen participants is a small fraction of a Phase 2 colorectal target, and the record marks that study terminated rather than completed. No results are posted for any of the three, and no Phase 3 study, marketing application or approval followed. A development programme that reaches Phase 2 and stops is informative, and what it most often means is that the compound did not show enough to continue — though the public record here does not state a reason, and a programme can also end for commercial reasons that say nothing about the molecule.

The Russian-language clinical literature

Reports of the free dipeptide in clinical use in the Russian Federation exist across several specialties, generally as uncontrolled series in journals with limited circulation elsewhere. None of it is described on this page, because none of it has been located in a form that supports specific statements about design, participant count or endpoint.

Thymogen Mechanism of Action

In vitro research

Monocyte and macrophage signalling. In the human monocytic THP-1 line, this dipeptide was one of five preparations from the series tested together. All five increased tyrosine phosphorylation of mitogen-activated cytoplasmic kinases, all five reduced lipopolysaccharide-stimulated expression of tumour necrosis factor and interleukin-6 in terminally differentiated cells, and all five reduced adhesion of the treated cells to activated endothelial monolayers [10]. The authors interpret the pattern as induction of tumour necrosis factor tolerance.

Two cautions attach. When five structurally different peptides all produce the same effect in the same assay, the shared result is as likely to reflect a property of the assay as a property of any one compound. And the paper is a collaboration involving the originator of the series, so it is not independent replication.

Transport modelling. A 2022 study docked this dipeptide, with twenty-five other ultrashort peptides, at the LAT1, LAT2 and PEPT1 transporters, and reported that the biologically active set scored higher than di- and tripeptides with no established activity [13]. The paper also raises the possibility that the antitumour effect reported for this dipeptide and three others could be connected to inhibition of those same transporters. That is a hypothesis generated by docking, offered as such.

Findings in this section were obtained in cultured cells and by computation.

Preclinical Research on Thymogen

Animal research

Lifespan and spontaneous tumours in rats

Seventy-six five-month-old outbred female rats were randomised to saline (32 animals) or 5 µg per rat of the dipeptide (44 animals), given subcutaneously five times a week for twelve months, and then monitored to natural death with microscopic examination of all tumours found [2].

What did not change: mean lifespan.

What did change: the lifespan of the top 10% of survivors rose from 949 ± 16.1 days to 1048 ± 21.1 days (p < 0.001); six of the 44 treated animals outlived the maximum lifespan of the controls; the ageing rate expressed as the Gompertz alpha fell from 0.0071 to 0.0041 per day; total tumour incidence was 1.5-fold lower (p < 0.01), malignant tumour incidence 1.7-fold lower (p < 0.01), and leukaemias and lymphomas 3.4-fold lower (p < 0.02) [2].

This is the most completely reported animal study in the batch — group sizes, a control arm, a defined schedule, natural-death follow-up and p values — and it should be read for what it separates. A compound that leaves mean lifespan untouched while extending the survival tail is doing something different from one that makes a population healthier on average. The tumour reduction is the firmer of the two results, and it is a rodent result in one outbred stock from one laboratory.

Haematopoietic progenitors in mice

Injection of the all-L dipeptide before irradiation did nothing to committed and pluripotent spleen colony-forming units in intact bone marrow; D-glutamate-containing isomers inhibited their proliferation; and the gamma-linked L-glutamate isomer with D-tryptophan stimulated them. Administration after irradiation of the all-L forms, or before irradiation of the D-forms, was reported to promote regeneration of the progenitor population [8, 9]. The pattern is the clearest structure–activity work located for any compound in this batch.

Liver injury models in rats

Two recent studies tested the dipeptide against analogues carrying D-alanine at the N- or C-terminus. In carbon tetrachloride hepatopathy, the peptides suppressed lipid peroxidation and stimulated reparative regeneration of hepatocytes, and the analogues outperformed the parent dipeptide, most so with the addition at the C-terminus [11]. In hydrazine hepatopathy, the lower of two amounts tested was effective while raising it produced no further effect, and again the C-terminal analogue was the strongest [12].

Both findings point away from this molecule rather than towards it: the papers are about improving on it. A non-monotonic amount–response is also worth noting, because it is not what a simple receptor interaction usually produces.

Findings in this section were obtained in rats and mice. Nothing in them establishes anything about humans.

What Is Thymogen Being Researched For?

  • Immune function — T-cell differentiation, cytokine output and phagocyte activation, the originating group's core claim [1].
  • Oncology, as oglufanide disodium — Kaposi's sarcoma, ovarian and colorectal cancer, on an antiangiogenic rationale [3, 4, 5, 6].
  • Geroprotection in rodents — lifespan and spontaneous tumour endpoints [2].
  • Stereochemistry of short peptides — the L and D forms and the alpha and gamma bonds, including the reciprocal-activity pairing with Thymodepressin [8, 7].
  • Experimental hepatotoxicity — as the comparator against modified analogues [11, 12].

None of that is research into, or evidence about, research-grade material supplied for laboratory use.

Current Research Status

Regulatory status (United States)
Not approved. Neither the free dipeptide nor its disodium salt has been approved by the U.S. Food and Drug Administration for any indication. The salt reached Phase 2 oncology trials in the United States under the code IM-862 and no approval followed. The free dipeptide is registered as a medicine in the Russian Federation, which is a separate regulatory category and carries no finding elsewhere.
Investigational status
Three studies of the disodium salt are registered on ClinicalTrials.gov: a completed Phase 1 study in recurrent ovarian cancer with 43 participants, a terminated Phase 2 study in metastatic colorectal cancer with 18 participants, and a Phase 2 ovarian and primary peritoneal study whose record has not been updated since it began. A separate randomised study in AIDS-related Kaposi's sarcoma with 44 participants is published in the Journal of Clinical Oncology. This is the only compound in the Khavinson bioregulator series with a registered clinical trial record.
Highest research phase reached
Phase 2 (as oglufanide disodium, development code IM-862). No Phase 3 study has been identified and no approval followed.
Approved uses
None
Approval is compound-specific
Yes

Status as of . This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

Chemical & Molecular Characteristics

Tryptophan changes the analytical picture completely. Unlike every other compound in this batch, this dipeptide contains an aromatic residue with strong absorbance near 280 nm. Ultraviolet quantification is straightforward, and an extinction coefficient can be estimated from the tryptophan content rather than relying on peptide-bond absorbance near 214 nm where buffers interfere. The same residue makes the molecule far better retained on reversed-phase columns than the polar tri- and tetrapeptides of this series, so a purity figure by HPLC means more here than it does for most of them.

Tryptophan is also the liability. The indole ring is the most oxidation-sensitive side chain in the standard set and is degraded by light, by peroxides and by residual oxidants from synthesis, giving oxindolylalanine, N-formylkynurenine and kynurenine products. Those are mass shifts of +16, +32 and +4 daltons, detectable by mass spectrometry if the analysis is looking for them, and a molecule of only 333 daltons carries a large proportional change when one of its two residues oxidises.

An N-terminal glutamate can cyclise. Free N-terminal glutamic acid residues cyclise to pyroglutamate with loss of water, which is favoured by heat and by acidic conditions and which caps the amine. The product has a distinct mass and distinct chromatographic behaviour.

The alpha versus gamma linkage is not cosmetic. The registered substance is the alpha-linked peptide, joined through the glutamate alpha-carboxyl. A gamma-linked isomer of the same two residues exists, has the same molecular formula and the same mass, and behaved differently from the alpha form in the haematopoietic work described above [8]. Mass spectrometry cannot distinguish them. This is one of the clearest cases in the library where composition confirmed by mass says nothing about identity.

Stereochemistry is the same problem one level deeper. L-Glu-L-Trp, D-Glu-D-Trp, L-Glu-D-Trp and D-Glu-L-Trp are four distinct substances of identical mass and formula that have been reported to act in different and sometimes opposite directions [9]. Optical rotation or a chiral separation, not a mass, is what distinguishes them.

Frequently Asked Questions

What is Thymogen?
A synthetic dipeptide, L-alpha-glutamyl-L-tryptophan, written Glu-Trp or EW. It was isolated from the calf thymus peptide complex Thymalin by reversed-phase chromatography and a preparation was then designed around the synthesised molecule [1]. PubChem records the free dipeptide as compound identifier 100094, with CAS registry number 38101-59-6 and FDA/NCATS unique ingredient identifier 4RHY598T5U.
Is Thymogen the same compound as oglufanide?
Yes, with a salt-form qualifier. Oglufanide is the International Nonproprietary Name for the free dipeptide; PubChem carries Thymogen, Timogen and oglufanide as names for the same record, compound identifier 100094. Oglufanide disodium is the disodium salt, a separate record — compound identifier 158780, CAS registry number 237068-57-4 — and it is the form that carried the development code IM-862 through clinical trials. The molecule is the same; the substance supplied is not necessarily.
How does Thymogen work?
Not established, and the literature carries two accounts that have never been reconciled. The originating group describes immunological activity: activation of T-cell differentiation, altered intracellular cyclic nucleotide composition, changed interleukin-2 and interferon output from blood lymphocytes, and activation of neutrophil chemotaxis and phagocytosis [1]. The oncology development programme described the same molecule as antiangiogenic [3]. No receptor has been identified for either account.
Is Thymogen FDA approved?
No. Neither the free dipeptide nor the disodium salt has been approved by the U.S. Food and Drug Administration for any indication. The salt reached Phase 2 oncology trials in the United States and no approval followed.
Has Thymogen been studied in clinical trials?
Yes — as the disodium salt, under the code IM-862, and this makes it the exception within its series. ClinicalTrials.gov carries a completed Phase 1 study in recurrent ovarian cancer with 43 participants [4], a terminated Phase 2 study in metastatic colorectal cancer with 18 participants [5], and a Phase 2 ovarian and primary peritoneal study [6]. A randomised study in 44 people with AIDS-related Kaposi's sarcoma is published in full [3].
What is Thymodepressin and how does it relate to Thymogen?
It is the mirror image. Thymodepressin is built from D-amino acids where Thymogen uses L-amino acids, and a 2024 review presents the pair as an unusual case of two enantiomeric preparations with reciprocal activity — one described as immunostimulant, the other as immunosuppressant [7]. Experimental work on haematopoietic progenitors reports the same pattern: L-Glu-containing dipeptides and D-Glu-containing dipeptides acted in opposite directions, and the type of peptide bond mattered as well as the optical form [8, 9]. Stereochemistry is not a detail for this compound.
How does Thymogen differ from Thymalin?
Thymalin is the calf thymus extract — a mixture obtained by mild acid extraction. Thymogen is one dipeptide isolated from that mixture and then synthesised [1]. The 1997 paper reports that the natural and synthetic preparations did not behave identically: both activated T-cell differentiation, but the synthetic dipeptides had no effect on antioxidant response in thymocytes where the natural peptides did. Findings about the extract are not findings about the dipeptide.
What identifiers are published for Thymogen?
For the free dipeptide: PubChem compound identifier 100094, CAS registry number 38101-59-6, FDA/NCATS unique ingredient identifier 4RHY598T5U, formula C16H19N3O5, average mass 333.34 g/mol. For the disodium salt: PubChem compound identifier 158780, CAS registry number 237068-57-4, unique ingredient identifier Q60AU1LLNU, formula C16H17N3Na2O5, average mass 377.30 g/mol.

Scientific References

  1. Morozov VG, Khavinson VK. Natural and synthetic thymic peptides as therapeutics for immune dysfunction International journal of immunopharmacology; 1997. PMID 9637345 doi:10.1016/s0192-0561(97)00058-1
  2. Anisimov VN, Khavinson VK, Morozov VG. Immunomodulatory synthetic dipeptide L-Glu-L-Trp slows down aging and inhibits spontaneous carcinogenesis in rats Biogerontology; 2000. PMID 11707921 doi:10.1023/a:1010042008969
  3. Tulpule A, Scadden DT, Espina BM, et al.. Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi's sarcoma Journal of clinical oncology : official journal of the American Society of Clinical Oncology; 2000. PMID 10673512 doi:10.1200/JCO.2000.18.4.716
  4. IM-862 in Treating Patients With Recurrent Ovarian Cancer 1999. NCT00003773
  5. Chemotherapy Plus IM-862 in Treating Patients With Metastatic Colorectal Cancer 1999. NCT00006037
  6. Combination Chemotherapy Plus IM-862 in Treating Patients With Resected Stage III Ovarian Cancer or Primary Peritoneal Cancer 2001. NCT00017303
  7. Deigin V, Linkova N, Vinogradova J, et al.. The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples International journal of molecular sciences; 2024. PMID 38732260 doi:10.3390/ijms25095042
  8. Deigin VI, Semenets TN, Zamulaeva IA, et al.. The effects of the EW dipeptide optical and chemical isomers on the CFU-S population in intact and irradiated mice International immunopharmacology; 2007. PMID 17276896 doi:10.1016/j.intimp.2006.11.010
  9. Semina OV, Semenets TN, Zamulaeva IA, et al.. Effects of structural and "mixed" isomers of Glu-Trp dipeptide on normal hemopoietic stem cells Bulletin of experimental biology and medicine; 2006. PMID 16984110 doi:10.1007/s10517-006-0141-0
  10. Avolio F, Martinotti S, Khavinson VK, et al.. Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line International journal of molecular sciences; 2022. PMID 35408963 doi:10.3390/ijms23073607
  11. Chulanova AA, Smakhtin MY, Bobyntsev II, et al.. Reparative and Antioxidant Effects of New Analogues of Immunomodulator Thymogen in Experimental Model of Liver Damage Bulletin of experimental biology and medicine; 2023. PMID 37861903 doi:10.1007/s10517-023-05929-5
  12. Chulanova AA, Smakhtina AM, Mal GS, et al.. Hepatoprotective Effects of Thymogen Analogues in Hydrazine Hepatopathy in Rats Bulletin of experimental biology and medicine; 2025. PMID 40442470 doi:10.1007/s10517-025-06405-y
  13. Khavinson V, Linkova N, Kozhevnikova E, et al.. Transport of Biologically Active Ultrashort Peptides Using POT and LAT Carriers International journal of molecular sciences; 2022. PMID 35887081 doi:10.3390/ijms23147733

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Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.