AC710

Inhibitor of CSF1R, FLT3, KIT, PDGFRB, PDGFRA

Structure

Information

  • CSF1R
  • FLT3
  • KIT
  • PDGFRB
  • PDGFRA
  • Inhibitor

In Vitro Validations

Uniprot ID: P07333
Target Class: Kinase
Target SubClass: TK
Potency: Kd
Potency Value: 0.5 nM
Potency Assay: Competition binding assay (KinomeScan)
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: yes
Target aliases:
Macrophage colony-stimulating factor 1 receptor, F ...

DOI Reference: 10.1021/ml300214g

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

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
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)
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP 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.

(last updated: 19 Mar 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

  • 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).

(last updated: 10 Apr 2021 )