AC220

Reagent Authentication Certificate:

Chemical Probes Portal AC220.pdf

Protein target name:

FLT3

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

1 nM - 300 nM

Probe Availability

MedChem Express (950769-58-1)

Cayman (950769-58-1)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:3765

Entrez gene ID:

2322

UNIPROT ID:

P36888

Target alias:

CD135, FLK-2, FLK2, STK1

Probe Details

Chemical Probes Portal ID:

CPP105

Probe alias:

Quizartinib, 950769-58-1, AC 220; AC-220

PubChem CID:

24889392

ChEMBL ID:

CHEMBL576982

SMILES string:

CC(C)(C)C1=CC(=NO1)NC(=O)NC2=CC=C(C=C2)C3=CN4C5=C(C=C(C=C5)OCCN6CCOCC6)SC4=N3

InChi Key:

CVWXJKQAOSCOAB-UHFFFAOYSA-N

Orthogonal probe:

G749

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

1.6 nM

Potency assay:

In vitro binding assay

Off target activity

Potency (off target):

Potency assay (off target):

AC220 was tested in Kinomescan panel of 402 kinases (binding assay) at 10 uM. Kinases that bound AC220 within 10-fold of FLT3 included KIT, PDGFRA, PDGFRb, RET, CSF1R and within 100-fold included FLT1, FLT4, DDR1, VEGFR2.

In cell validation

On target activity in cells

Potency in cells:

IC50

4.2 nM

Potency assay (cells):

Inhibition of FLT3 autophosphorylation in MV4-11 and RS4;11 cells.

Target engagement assay (cells):

Indirect, inhibition of autophosphorylation

Off target activity in cells

Potency assay, off target (cells):

AC220 was at least 10-fold selective for FLT3 > KIT, PDGFRA/B, RET, and CSFR1.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

No growth inhibition was detected in A375 cells.

In vivo validation

Organism:

Nude (nu/nu) mice

Dose:

10 mg/mL

Route of delivery:

Oral

Plasma half life:

~4 h

Fraction of probe bound to plasma protein:

0.01

Cmax:

2100 ng/mL

Tmax:

1.5 h

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Inhibition of autophosphorylation in xenograft

Primary Reference

Reference (doi):

10.1182/blood-2009-05-222034

Reference (PMID):

19654408

External Resources

Available data:

GDSC1

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

No nonhuman ortholog potencies were reported. Acute oral dosing in mice was shown be tolerated (up to 300 mg/kg), though PK was linear up through 100 mg/kg. Repeat dosing was only performed at 10 mg/kg. RET, PDGFRA, PDGFRB, CSF1R are the only kinases within 10x. The recommended upper in vitro concentration is intended to minimize off-target RTK activity.

Jun 10 2016 - 4:13am

AC220 is potent and selective and has good PK characteristics. While activity in certain biochemical assays and cellular assays may be evident as low as 0.1-10 nM, drug-resistant models may require concentrations as high as 100-300 nM. It has been compared with and/or combined with other anticancer agents such as G-749 (FLT3 inhibitor) and JQ1 (BET protein antagonist) in various models, with resistant AML being an initial disease target in humans.

Jun 10 2016 - 4:14am

This probe has a number of targets other than FLT3 and is active at 300 nM in human primary cell assays that do not express FLT3. If used as a target-selective probe in a study, this data should be supplemented by target knock-down and over expression of a constitutively active form to confirm involvement of the target.

Jun 10 2016 - 4:14am

AC220

Probe Availability

Probe Information

Target Details

CD135, FLK-2, FLK2, STK1

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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AC220

Probe Availability

Probe Information

Target Details

CD135, FLK-2, FLK2, STK1

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?