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Fig. 1 · Structure
Cat. No.
A13691
CAS No.
1232030-35-1
Formula
C25H23Cl2FN6O
Mol. Weight
513.39

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FRAX486

Cat. No. A13691 CAS 1232030-35-1

PAK inhibitor

FRAX486 is a small-molecule PAK inhibitor.

In Stock

Publications for FRAX486

2 publications citing this product

  1. Natalia Barraza-Núñez, .et al. , Neurotox Res, 2023, Mar 3 PMID: 36867391
  2. Yukie Yamahashi, .et al. , Mol Psychiatry, 2022, 03 June PMID: 35665767
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Biological Activity

Bioactivity / Mechanism

FRAX486 inhibits group I PAKs in a biochemical peptide-phosphorylation assay, with reported IC50 values of 8.25 nM for PAK1, 39.5 nM for PAK2 and 55.3 nM for PAK3. PAK4 inhibition was weaker (IC50 779 nM). This comparison establishes relative potency across the four tested isoforms, rather than comprehensive kinase selectivity. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
PAK1 14 nM
PAK2 33 nM
PAK3 39 nM
PAK4 575 nM

In Vitro Studies

In primary fibroblasts from two subjects with activating PAK1 variants, FRAX486 (50 nM, 1 h pretreatment) reduced the proportion of filopodia-rich cells and increased round morphology during early cell spreading. The intermediate-morphology category did not differ significantly across the tested groups. This result concerns a cellular morphology phenotype and does not demonstrate patient benefit. [2]

Biochemical inhibition of PAK1–4

Biochemical assay · Full-length PAK1, PAK2, PAK3 and PAK4 kinase assays [1]

FRAX486 inhibited group I PAK1–3 more potently than PAK4 in this four-isoform comparison. These are biochemical IC50 values, not cellular treatment concentrations.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
PAK1 peptide-substrate phosphorylation inhibitionIC50 8.25 nM[1]
PAK2 peptide-substrate phosphorylation inhibitionIC50 39.5 nM[1]
PAK3 peptide-substrate phosphorylation inhibitionIC50 55.3 nM[1]
PAK4 peptide-substrate phosphorylation inhibitionIC50 779 nM[1]

Literature-Reported Treatment Conditions

Treatment concentration
Ten FRAX486 titrations; reported IC50 values are assay endpoints.
Method
Invitrogen SelectScreen Z′-LYTE functional biochemical kinase assay; variable-slope sigmoidal dose–response fitting.
Reported limits
Assay duration, ATP concentration, enzyme concentrations and solvent conditions are not specified in the acquired main-text assay description.
Methods and source locations

Compound reported in the paper: FRAX486

Evidence concerns the reported research material; it does not establish performance or purity of an Adooq lot.

Figure 1B–F and caption; Results, Discovery of an Inhibitor of Group I PAKs; Materials and Methods, biochemical assay paragraph

PAK1 peptide-substrate phosphorylation inhibition: Functional Z′-LYTE kinase assay; ten titrations; curves plotted as mean ± SEM (n = 2). Values transcribed from caption, not estimated from curves. — Figure 1B–F and caption; Results, Discovery of an Inhibitor of Group I PAKs; Materials and Methods, biochemical assay paragraph

PAK2 peptide-substrate phosphorylation inhibition: Functional Z′-LYTE kinase assay; ten titrations; curves plotted as mean ± SEM (n = 2). Values transcribed from caption, not estimated from curves. — Figure 1B–F and caption; Results, Discovery of an Inhibitor of Group I PAKs; Materials and Methods, biochemical assay paragraph

PAK3 peptide-substrate phosphorylation inhibition: Functional Z′-LYTE kinase assay; ten titrations; curves plotted as mean ± SEM (n = 2). Values transcribed from caption, not estimated from curves. — Figure 1B–F and caption; Results, Discovery of an Inhibitor of Group I PAKs; Materials and Methods, biochemical assay paragraph

PAK4 peptide-substrate phosphorylation inhibition: Functional Z′-LYTE kinase assay; ten titrations; curves plotted as mean ± SEM (n = 2). Values transcribed from caption, not estimated from curves. — Figure 1B–F and caption; Results, Discovery of an Inhibitor of Group I PAKs; Materials and Methods, biochemical assay paragraph

Morphology during spreading of PAK1-mutant fibroblasts

Cell-based study · Primary skin fibroblasts from two subjects carrying PAK1 p.Tyr131Cys or p.Tyr429Cys and two healthy controls [2]

FRAX486 shifted the predominance of filopodia-rich (spiky) morphology toward round morphology in subject fibroblasts. This ex vivo human-cell observation does not show treatment efficacy in patients.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Proportions of subject fibroblasts classified by morphologyPercentage of cells DMSO: spiky 33%–43%, round 31%–40%, intermediate 27%–28%. FRAX486: spiky 13%–19%, round 57%–66%, intermediate 22%–25%.[2]
Morphology categories across all Figure 5C groupsOne-way ANOVA Spiky: P < 0.0001, F(7,21) = 56.84; round: P < 0.0001, F(7,21) = 13.24; intermediate: P = 0.7278, F(7,21) = 0.6146.[2]

Literature-Reported Treatment Conditions

Treatment concentration
50 nM
Exposure duration
1 h pretreatment before cell spreading; morphology assessed 30 min after plating.
Method
Cell-spreading assay on fibronectin-coated coverslips; phalloidin F-actin staining and epifluorescence microscopy; predefined spiky, intermediate and round categories.
Vehicle
DMSO; DMSO-alone control
Reported limits
Final DMSO percentage, FRAX486 salt/counterion and analytical purity are not specified in the relevant acquired methods.
Methods and source locations

Compound reported in the paper: FRAX486

Evidence concerns the reported research material; it does not establish performance or purity of an Adooq lot.

Methods, Cell Lines and Culturing Conditions and Cell-Spreading Assay; Figure 5A–C and caption; Results, Treatment of Subject Cells with PAK1 Inhibitor Reverts the Cellular Morphology Phenotype

Proportions of subject fibroblasts classified by morphology: Ranges across two subject-derived lines as reported in Results; Figure 5C shows means ± SD over four independent experiments with 50 cells per line/condition/experiment. Round means >50% perimeter occupied by lamellipodia/ruffles; spiky means >50% occupied by filopodia. — Methods, Cell Lines and Culturing Conditions and Cell-Spreading Assay; Figure 5A–C and caption; Results, Treatment of Subject Cells with PAK1 Inhibitor Reverts the Cellular Morphology Phenotype

Morphology categories across all Figure 5C groups: ANOVA conducted separately for each morphology category, followed by Bonferroni post hoc tests; these omnibus statistics are not individual treated-versus-vehicle pairwise P values. — Methods, Cell Lines and Culturing Conditions and Cell-Spreading Assay; Figure 5A–C and caption; Results, Treatment of Subject Cells with PAK1 Inhibitor Reverts the Cellular Morphology Phenotype

In Vivo Studies

A single subcutaneous dose of FRAX486 (20 mg/kg) reduced elevated apical dendritic-spine density in adult male Fmr1-knockout mice 8 h later. The effect was confined to segment 3 and neighboring segment 4 of the assessed temporal-cortex dendrites; segments 1–2 and 5–10 showed no effect. The findings describe a regional morphological response in this mouse model. [1]

Acute cortical apical-spine response in Fmr1-knockout mice

Animal study · 11-week-old male Fmr1-knockout and wild-type mice on an FVB background; layer II/III temporal-cortex pyramidal neurons [1]

After a single FRAX486 administration, elevated apical spine density in knockout mice was reduced in segment 3 and neighboring segment 4. No effect was reported in apical segments 1–2 and 5–10. This experiment measures morphology rather than cognition or clinical benefit.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Apical spine density, segment 3Group comparison WT + vehicle vs KO + vehicle: P < 0.05; KO + vehicle vs KO + FRAX486: P < 0.001; WT + vehicle vs KO + FRAX486: P > 0.05. One-way ANOVA across three groups: P = 0.0004.[1]
Regional distribution of the apical-spine responseGroup comparison Segment 4, KO + vehicle vs KO + drug: P < 0.05. No effect reported in segments 1–2 and 5–10.[1]

Conditions shared by the study groups

Route
Subcutaneous injection
Frequency
Single administration
Treatment course
8 h to tissue collection
Vehicle
20% (wt/vol) hydroxypropyl-β-cyclodextrin
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
Fmr1 KO + FRAX486
20 mg/kg		Fmr1 KO + vehicle (6 mice, 60 neurons) and WT + vehicle (4 mice, 40 neurons)Apical segment 3 spine density reduced versus KO + vehicle; not significantly different from WT + vehicle. Treated KO: 6 mice, 60 neurons. Segment 4 also decreased; remaining assessed segments did not show a treatment effect.[1]
Fmr1 KO + FRAX486
Model: 11-week-old male Fmr1-knockout and wild-type mice on an FVB background; layer II/III temporal-cortex pyramidal neurons
Reported limits: Randomization and blinding are not specified in the acquired main text.
Methods and source locations

Compound reported in the paper: FRAX486

Evidence concerns the reported research material; it does not establish performance or purity of an Adooq lot.

Figure 3A–C and caption; Results, FRAX486 Rescues the Dendritic Spine Abnormality in Fmr1 KO Mice (first two paragraphs); Materials and Methods, animal/drug and Golgi-Cox paragraphs

Apical spine density, segment 3: Golgi-Cox morphology; mean ± SEM; WT + vehicle: 40 neurons from 4 mice; KO + vehicle: 60 neurons from 6 mice; KO + drug: 60 neurons from 6 mice; Tukey multiple-comparison post hoc test. — Figure 3A–C and caption; Results, FRAX486 Rescues the Dendritic Spine Abnormality in Fmr1 KO Mice (first two paragraphs); Materials and Methods, animal/drug and Golgi-Cox paragraphs

Regional distribution of the apical-spine response: Same Figure 3 experiment; ten 10-µm dendritic segments; no new experiment counted for other segments. — Figure 3A–C and caption; Results, FRAX486 Rescues the Dendritic Spine Abnormality in Fmr1 KO Mice (first two paragraphs); Materials and Methods, animal/drug and Golgi-Cox paragraphs

Fmr1 KO + FRAX486 · Figure 3A–C and caption; Results, FRAX486 Rescues the Dendritic Spine Abnormality in Fmr1 KO Mice (first two paragraphs); Materials and Methods, animal/drug and Golgi-Cox paragraphs

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 1232030-35-1
Applications PAK inhibitor
Formula C25H23Cl2FN6O
Molecular Weight 513.39
SMILES
CCN1C2=NC(=NC=C2C=C(C1=O)C3=C(C=C(C=C3)Cl)Cl)NC4=CC(=C(C=C4)N5CCNCC5)F

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 21 mg/mL (40.9 mM)
Water Insoluble
Ethanol Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Bridget M Dolan, Sergio G Duron, David A Campbell, et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486 Proceedings of the National Academy of Sciences of the United States of America (2013). PMID: 23509247 DOI: 10.1073/pnas.1219383110 Source material
  2. [2] Frederike L Harms, Katja Kloth, Annette Bley, et al. Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder American Journal of Human Genetics (2018). PMID: 30290153 DOI: 10.1016/j.ajhg.2018.09.005 Source material

Publications

2 publications citing this product

  1. Natalia Barraza-Núñez, .et al. , Neurotox Res, 2023, Mar 3 PMID: 36867391
  2. Yukie Yamahashi, .et al. , Mol Psychiatry, 2022, 03 June PMID: 35665767

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