Dihexa (PNB-0408)

Verified against PubChem PUG REST, CID 129010512, properties and synonym records retrieved 17 August 2026. Fields marked “not verified” are ones we could not confirm against a primary chemical database — we leave them blank rather than guess.

Chemical identity

Nothing about Dihexa's identity is in dispute. A single PubChem record carries the name, and it carries everything else with it: CID 129010512, CAS 1401708-83-5, formula C27H44N4O5, molecular weight 504.7 g/mol, InChIKey XEUVNVNAVKZSPT-JTJYXVOQSA-N, UNII 9WYX65A5C2. The IUPAC name on that record runs (2S,3S)-N-(6-amino-6-oxohexyl)-2-[[(2S)-2-(hexanoylamino)-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanamide, which is the systematic form of the shorthand Hexanoyl-Tyr-Ile-Ahx-NH2.

The catalogue designations PNB-0408 and ATH-1001 both appear in the synonym list attached to that same CID, so the two codes denote one molecule. The structure is a three-part chain: an N-hexanoyl cap, a tyrosine-isoleucine dipeptide, and a C-terminal 6-aminohexanoic amide tail. That architecture derives from the Nle-Tyr-Ile N-terminal fragment of norleucine-1-angiotensin IV. The stated design intent, described in McCoy 2013, was to raise hydrophobicity and reduce hydrogen-bonding capacity so the fragment would survive metabolism and cross barriers that the parent peptide could not. McCoy 2013 is one of the four flagged papers, and the only one whose notice remains unresolved; the next section sets out the record.

Four formal integrity flags on the foundational record

Four papers from the originating laboratory, all published in the Journal of Pharmacology and Experimental Therapeutics, carry formal integrity flags. All four received Notices of Concern printed in September 2021 at 378(3):311 through 314 (PMIDs 34551987, 34551988, 34551989 and 34551990). Three were then retracted in April 2025: Kawas and colleagues 2011, the anti-Met and anticancer report (retraction notice at 392(4):103568, PMID 40312094); Kawas and colleagues 2012, on the development of the analogue series (392(4):103566, PMID 40312092); and Benoist and colleagues 2014, the paper that reported HGF binding and c-Met dependence for this molecule (392(4):103567, PMID 40312093). PubMed types all three as Retracted Publication, and the retracted full texts are no longer served through PubMed Central.

McCoy and colleagues 2013 is the exception. It carries the September 2021 Notice of Concern and nothing since; PubMed does not type it as a Retracted Publication. That is the paper describing the synthesis, the metabolic-stability measurements and the scopolamine and aged-rat behavioural readouts. The three withdrawn papers supplied the proposed mechanism and the analogue development work; the one still standing supplied the molecule and the behaviour, and its flag has been unresolved for close to five years. A Notice of Concern asserts neither invalidity nor innocence — it records that a question was raised and not settled.

This governs how any downstream claim is weighted. The papers that between them supplied the synthesis, the metabolic-stability data, the behavioural data and the proposed mechanism are all flagged, and three of the four are withdrawn outright. Secondary pages that mention only the 2025 retraction of the binding paper understate the position of the record.

What the HGF pathway framing rests on now

With Benoist 2014 withdrawn, the surviving support for HGF-pathway involvement is indirect and comes from independent groups. In larval zebrafish, Uribe and colleagues 2015 reported that protection of lateral-line hair cells against neomycin and gentamicin was attenuated by co-treatment with the HGF antagonist 6-AH, and partially attenuated by inhibitors of Akt, TOR and MEK; pre-treatment did not change uptake of fluorescently tagged gentamicin into hair cells, which the authors read as an intracellular rather than an entry-blocking effect.

In APP/PS1 mice, Sun and colleagues 2021 reported changes in synaptophysin expression, astrocyte and microglial activation markers and cytokine levels, and reported that the PI3K inhibitor wortmannin reversed the anti-inflammatory and anti-apoptotic readouts, which the authors framed as PI3K/AKT involvement.

None of these re-established direct binding of the molecule to HGF, which was the specific finding in the retracted paper. They are consistent with engagement somewhere on that signalling axis, and they are not a replacement for the withdrawn binding data.

Use as a laboratory reagent outside neuroscience

A distinct and less contested strand of the literature uses this molecule simply as a bench reagent. Siller and colleagues 2015 built a growth-factor-free protocol for differentiating human pluripotent stem cells toward hepatocyte-like cells, using Dihexa together with dexamethasone at the hepatoblast-to-hepatocyte step in place of recombinant HGF. Mathapati and colleagues 2016 published the same approach as a formal methods protocol, and Pan and colleagues 2022 incorporated it into a Vitamin C, Dihexa and forskolin combination for hepatic specification.

In a rat sciatic-nerve transection and repair model, Weiss and colleagues 2021 tested mesenchymal stem cells, G-CSF and Dihexa alone and in combination across ten groups of male Lewis rats. Motor function by walking foot-print grading at 8 to 16 weeks was reported as significantly better where stem cells plus Dihexa were delivered into gastrocnemius muscle.

In these settings the molecule functions as a substitute for a recombinant growth factor in culture or as an adjunct in a surgical model. That use does not depend on the retracted behavioural claims.

Null findings, and the fosgonimeton distinction

Not every model produced a positive readout. Wells and colleagues 2024 randomised 40 male Wistar rats into vehicle, 3-nitropropionic acid, and 3-NP plus PNB-0408 groups and tracked body weight, motor function and cognition over five weeks before histopathology. The authors reported that PNB-0408 did not protect the animals from 3-NP-induced deficits, and concluded it may not be an efficacious strategy in that Huntington's-like model.

Human data in this chemical space belong to a different molecule. Fosgonimeton (ATH-1017) is a prodrug developed by Athira Pharma, now LeonaBio. Its Phase 2/3 LIFT-AD study, NCT04488419, enrolled 554 participants and completed in July 2024. Topline data announced in September 2024 reported that the trial did not meet its primary endpoint, a Global Statistical Test combining ADAS-Cog11 and ADCS-ADL23, nor those two key secondary endpoints, at 26 weeks.

A ClinicalTrials.gov intervention search across Dihexa, PNB-0408 and ATH-1001 returned zero registered studies. Fosgonimeton findings are not transferable to Dihexa.

What is not known

There is no human data of any kind on this molecule. A ClinicalTrials.gov intervention search across Dihexa, PNB-0408 and ATH-1001 returned zero registered studies, so no dose-ranging, pharmacokinetic, safety or efficacy work in people has been registered, let alone reported. The preclinical literature is small: a PubMed search for the term returns 18 records, of which two are false matches to unrelated lipid chemistry and several are reviews by the originating group rather than independent data. Sample sizes are frequently absent from the retrieved reports, and only the Huntington's-model study and the sciatic-nerve study state group numbers explicitly. No study characterised chronic administration, reproductive or developmental effects, carcinogenicity, immunogenicity, or behaviour in aged or diseased non-rodent species. The direct HGF-binding claim that underpinned the proposed mechanism was withdrawn with the 2025 retraction and has not been independently reproduced. Because the second foundational paper also carries a notice of concern, the metabolic-stability and barrier-permeability characterisations that the rest of the field builds on have themselves not been independently confirmed.

Questions