TrkA and TrkB positive modulator
Pharmaceutical compound
ACD856 , orACD-856 , is atropomyosin receptor kinase TrkA ,TrkB , andTrkC positive allosteric modulator which is under development for the treatment ofAlzheimer's disease ,depressive disorders ,sleep disorders , andtraumatic brain injuries .[ 1] [ 3] [ 2] [ 5] [ 6] [ 4] by mouth .[ 1] [ 2]
The drug potentiates thetropomyosin receptor kinases TrkA ,TrkB , andTrkC withEC50 Tooltip half-maximal effective concentration values of 382 nM, 295 nM, and ~330 nM, respectively.[ 2] [ 4] brain-derived neurotrophic factor (BDNF) andnerve growth factor (NGF).[ 6] [ 2] [ 7]
In addition to the tropomyosin receptor kinases, ACD856 is also a similarlypotent positive allosteric modulator of certain otherreceptor tyrosine kinases , including theinsulin-like growth factor 1 receptor (IGF1R) and thefibroblast growth factor receptor 1 (FGFR1).[ 4] efficacies at the IGF1R and FGFR1 were much lower than at the TrkA, TrkB, and TrkC.[ 4]
In animals, ACD856 has been found to reversescopolamine - anddizocilpine (MK-801)-inducedmemory impairment , to improveage -relatedmemory deficits , and to have sustainedantidepressant -like activity.[ 5] [ 2] [ 7] [ 8] [ 4] neuroprotective properties.[ 5] [ 7]
In humans, the drug has been shown to cross theblood–brain barrier and to inducedose-dependent changes inelectroencephalogram parameters.[ 5] [ 2] [ 9] tolerability orsafety concerns have been identified inpreclinical research orphase 1 clinical trials .[ 10] pharmacokinetics have been characterized and itselimination half-life is approximately 19 hours.[ 5] [ 11] [ 9]
Thechemical structure of ACD856 has not yet been disclosed as of 2024, but the structure of its predecessorponazuril (ACD855) is known and both ponazuril and ACD856 have been described astriazinetriones .[ 5] [ 7]
It was discovered through the use ofhigh-throughput screening of 25,000 compounds.[ 5] [ 2] [ 4] Toltrazuril andponazuril (ACD855), twoveterinary antiparasitic agents , were identified as possessing Trk-potentiating activity with this screen in 2013.[ 2] [ 5] [ 4] derived viastructural optimization of these compounds.[ 2] [ 5] [ 11] scientific literature by 2021.[ 4] [ 12]
As of May 2024, ACD856 is inphase 1 clinical trials for Alzheimer's disease and is in thepreclinical stage of development for depressive disorders, sleep disorders, and traumatic brain injuries.[ 1] [ 3] [ 2] [ 10] phase 2 clinical trial for Alzheimer's disease is being planned as of May 2024.[ 1] [ 1] [ 3] [ 2]
^a b c d e f g "ACD 856" .AdisInsight . Springer Nature Switzerland AG. 17 May 2024. Retrieved23 October 2024 .^a b c d e f g h i j k l m "ACD856" .ALZFORUM . 19 December 2023. Retrieved23 October 2024 .^a b c d "Delving into the Latest Updates on ACD-856 with Synapse" .Synapse . 12 October 2024. Retrieved23 October 2024 .^a b c d e f g h i Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, et al. (July 2021)."Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction" .Cells .10 (8): 1871.doi :10.3390/cells10081871 PMC 8391421 PMID 34440640 . ^a b c d e f g h i j Forsell P, Parrado Fernández C, Nilsson B, Sandin J, Nordvall G, Segerdahl M (July 2024)."Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease" .Pharmaceuticals .17 (8): 997.doi :10.3390/ph17080997 PMC 11357672 PMID 39204102 . ^a b Wang D, Lang ZC, Wei SN, Wang W, Zhang H (2 May 2024)."Targeting brain-derived neurotrophic factor in the treatment of neurodegenerative diseases: A review" .Neuroprotection .2 (2). Wiley:67– 78.doi :10.1002/nep3.43 ISSN 2770-7296 .ACD856 is an innovative allosteric modulator that positively affects all Trk receptors, amplifying their kinase activity. Subsequently, it potentiates the effect of BDNF or nerve growth factor (NGF) on neuronal survival, function, and plasticity of synapses. The finished phase I study showed that ACD856 passed the blood‐brain barrier and induced dose‐dependent treatment‐related alterations in quantitative electroencephalogram parameters with good safety.141,142 ^a b c d Parrado Fernandez C, Juric S, Backlund M, Dahlström M, Madjid N, Lidell V, et al. (July 2023)."Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer's Disease" .International Journal of Molecular Sciences .24 (13) 11159.doi :10.3390/ijms241311159 PMC 10342804 PMID 37446337 . ^ Madjid N, Lidell V, Nordvall G, Lindskog M, Ögren SO, Forsell P, et al. (August 2023)."Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling - a potential therapeutic concept?" .Psychopharmacology .240 (8):1789– 1804.doi :10.1007/s00213-023-06410-x .PMC 10349764 PMID 37394539 . ^a b Önnestam K, Nilsson B, Rother M, Rein-Hedin E, Bylund J, Anderer P, et al. (2023)."Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects" .The Journal of Prevention of Alzheimer's Disease .10 (4):778– 789.doi :10.14283/jpad.2023.89 .PMID 37874100 . ^a b Nordvall G, Forsell P, Sandin J (October 2022)."Neurotrophin-targeted therapeutics: A gateway to cognition and more?" .Drug Discovery Today .27 (10) 103318.doi :10.1016/j.drudis.2022.07.003 PMID 35850433 . ^a b Nilsson B, Bylund J, Halldin MM, Rother M, Rein-Hedin E, Önnestam K, et al. (May 2024)."ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics" .European Journal of Clinical Pharmacology .80 (5):717– 727.doi :10.1007/s00228-024-03645-1 .PMC 11001683 PMID 38353689 . ^ Nordvall G, Madjid N, Backlund M, Halldin M, Rother M, Nilsson B, et al. (2021)."ACD856: A novel positive allosteric modulator of Trk-signaling in clinical development for the treatment of Alzheimer's disease" .Alzheimer's & Dementia .17 (S9) e057730. Wiley.doi :10.1002/alz.057730 ISSN 1552-5260 .
Angiopoietin CNTF EGF (ErbB)
FGF
FGFR1 FGFR2 Agonists: Ersofermin FGF (1 ,2 (bFGF) ,3 ,4 ,5 ,6 ,7 (KGF ),8 ,9 ,10 (KGF2) ,17 ,18 ,22 )Palifermin Repifermin Selpercatinib Sprifermin Trafermin FGFR3 FGFR4 Unsorted
HGF (c-Met) IGF
LNGF (p75NTR ) PDGF RET (GFL)
SCF (c-Kit) TGFβ Trk
TrkA Negative allosteric modulators: VM-902A TrkB Agonists: 3,7-DHF 3,7,8,2'-THF 4'-DMA-7,8-DHF 7,3'-DHF 7,8-DHF 7,8,2'-THF 7,8,3'-THF Amitriptyline Braegen-02 BDNF BNN-20 Deoxygedunin Diosmetin DMAQ-B1 HIOC LM22A-4 N-Acetylserotonin NT-3 NT-4 Norwogonin (5,7,8-THF) R7 R13 (BrAD-R13, Braegen-01) TDP6 TrkC Positive allosteric modulators: ACD856
VEGF Others Additional growth factors: Adrenomedullin Colony-stimulating factors (seehere instead)Connective tissue growth factor (CTGF) Ephrins (A1 ,A2 ,A3 ,A4 ,A5 ,B1 ,B2 ,B3 )Erythropoietin (seehere instead)Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF) Glia maturation factor (GMF) Hepatoma-derived growth factor (HDGF) Interleukins /T-cell growth factors (seehere instead)Leukemia inhibitory factor (LIF) Macrophage-stimulating protein (MSP; HLP, HGFLP) Midkine (NEGF2) Migration-stimulating factor (MSF; PRG4) Oncomodulin Pituitary adenylate cyclase-activating peptide (PACAP) Pleiotrophin Renalase Thrombopoietin (seehere instead)Wnt signaling proteins Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)
