AC710

Protein target name:

PDGFRα, PDGFRβ, KIT, FLT3, CSF1R

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

100 nM

Probe Availability

MedChemExpress

TOCRIS

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:2433 HGNC:3765 HGNC:6342 HGNC:8804 HGNC:8803

Entrez gene ID:

1436 2322 3815 5159 5156

UNIPROT ID:

P07333 P36888 P10721 P09619 P16234

Target alias:

FMS; CSFR; FIM2; HDLS; C-FMS; CD115; CSF-1R; BANDDOS; M-CSF-R; FLK2; STK1; CD135; FLK-2; PBT; SCFR; C-Kit; CD117; MASTC; MF1; KOGS; IBGC4; JTK12; PDGFR; PENTT; CD140B; PDGFR1; PDGFR-1; CD140A; PDGFR2; PDGFR-2

Probe Details

Chemical Probes Portal ID:

CPP1193

Probe alias:

cpd 22b

PubChem CID:

54760053

ChEMBL ID:

CHEMBL2206278

SMILES string:

CCN1C(CC(CC1(C)C)OC2=CN=C(C=C2)C(=O)NC3=CC=C(C=C3)NC(=O)NC4=NOC(=C4)C(C)(C)C)(C)C

InChi Key:

JVCWPUFNLFSKFS-UHFFFAOYSA-N

Physico-chemical properties

Solubility - concentration:

1 mg/mL in water

NMR:

1 H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.51 (s, 1H), 8.83 (s, 1H), 8.41 (d, J = 2.83 Hz, 1H), 8.13 (d, J = 8.85 Hz, 1H), 7.99 (br. s., 1H), 7.81 (d, J = 9.04 Hz, 2H), 7.72 (dd, J = 2.83, 8.85 Hz, 1H), 7.43 (d, J = 8.85 Hz, 2H), 6.50 (s, 1H), 5.04 - 5.27 (m, 1H), 3.32 (br. s., 2H), 2.39-2.24 (m, 2H), 2.32 (s, 3H), 1.96 (t, J = 12.34 Hz, 2H), 1.48 (d, J = 10.74 Hz, 12H), 1.34 (t, 3H), 1.30 (s, 9H)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.5-1.6 nM PDGFRα, PDGFRβ, KIT, FLT3, CSF1R

Potency assay:

Competition binding assay (KinomeScan)

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

Selectivity determined against a panel of 386 unique kinases @ 1 uM. Kinase Binding Affinities (< 1,000 nM) in nM: DDR1 415, FLT1 606, FLT4 93.5, MKNK2 293, MUSK 218, RET 33.8, VEGFR2 229, YSK4 147, ZAK 64.4

In cell validation

On target activity in cells

Potency in cells:

IC50

1.2 nM KIT, 2 nM FLT3, 7.7 nM PDGFRβ, 10.5 nM CSF1R, 46.3 nM (Cell Prol)

Potency assay (cells):

M-NFS-60 cell proliferation assay, CSF1R phosphorylation MSD assay

Off target activity in cells

Probe Selectivity in Cell:

pFLT3 IC50 2 in MV4-11, pKIT IC50 1.2 in H526, pPDGFRβ IC50 7.7 in MG-63 cells. Clean cytochrome P450 inhibition profiles (IC50 values > 40 μM) against a panel of five isoforms (1A2, 2C9, 2C19, 2D6, and 3A4). No Cyp induction was observed for 22b when tested at 3 and 30 μM concentrations against three isoforms (1A2, 2D6, and 3A4)

In vivo validation

Organism:

Mouse

Dose:

3, 10, 30 mg/Kg

Route of delivery:

Intraperitoneal

Systemic clearance:

14 mL/min/Kg

Fraction of probe bound to plasma protein:

44 %

Primary Reference

Reference (doi):

10.1021/ml300214g

Reference (PMID):

24900421

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

The probe binds with selectivity for kinases of the PDGFR family. The selectivity of the inhibitor for this family of kinases is based on affinity (Kd) studies against a panel of 386 kinases. The ability of AC710 to inhibit kinase activity was measured by auto-phosphorylation of CSFR1. This should be confirmed for other kinases within the family. The efficacy of the compound in cells and mice was determined based on cell growth and tumour volume, respectively. It has not been confirmed that the growth inhibition effects of AC710 in cells and mice are mediated through inhibition of kinase activity. When using this compound, the kinase activity of the intended target protein should be assessed to ensure that AC710 is acting through PDGFR kinases to mediate any observed phenotypes.

Mar 19 2021 - 12:19pm

Potent PDGFR family inhibitor (cell “close to target assay” IC50 values are 1.2, 2, 7.7 and 10.5 nM for KIT, FLT3, PDGFRβ and CSF1R respectively in H526,MV411,MG-63, and M-NFS-60 cells, respectively (phosphorylation MSD assay?). (Kd = 1.3 nM for PDGFRα)
Cell potency “close to phenotype” (viability) in M-NFS-60 (CSF1R driven) is 46 nM
Was developed by Ambit later Daiichi Sankyo as a preclinical candidate for cancer or inflammatory diseases. Daiichi Sankyo have developed Pexidartinib with a similar CSF1R/Flt3/cKit profile in phase 3 clinical development.
Exhibits >30-fold selectivity over a panel of 386 kinases using Ambit KinomeScan.
Exhibits no activity against cytochrome P450 (5 isoforms)
Good oral bioavailability in mice/rat; F=44% (rat)
Causes dose dependent tumor regression of leukemia cell xenografts in mice ( M-NFS-60 cells) at doses from 0.3 mg/kg
Reduces joint swelling and inflammation in a mouse model of collagen-induced arthritis at doses from 3 mg/kg (same effect as dexamethasone 0.1 mg/kg).

Apr 10 2021 - 1:08pm

AC710

Probe Availability

Probe Information

Target Details

FMS; CSFR; FIM2; HDLS; C-FMS; CD115; CSF-1R; BANDDOS; M-CSF-R; FLK2; STK1; CD135; FLK-2; PBT; SCFR; C-Kit; CD117; MASTC; MF1; KOGS; IBGC4; JTK12; PDGFR; PENTT; CD140B; PDGFR1; PDGFR-1; CD140A; PDGFR2; PDGFR-2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

Search form

AC710

Probe Availability

Probe Information

Target Details

FMS; CSFR; FIM2; HDLS; C-FMS; CD115; CSF-1R; BANDDOS; M-CSF-R; FLK2; STK1; CD135; FLK-2; PBT; SCFR; C-Kit; CD117; MASTC; MF1; KOGS; IBGC4; JTK12; PDGFR; PENTT; CD140B; PDGFR1; PDGFR-1; CD140A; PDGFR2; PDGFR-2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?