QC6352

Protein target name:

KDM4C

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 100 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Protein Demethylase

HUGO ID:

HGNC:17071

Entrez gene ID:

23081

UNIPROT ID:

Q9H3R0

Target alias:

GASC1; JHDM3C; JMJD2C; TDRD14C

Probe Details

Chemical Probes Portal ID:

CPP2058

Probe alias:

9DJ, cpd 6

PubChem CID:

118598059

ChEMBL ID:

CHEMBL4216044

SMILES string:

O=C(C1=C(NC[C@@H]2CCCC3=C2C=CC(N(C)C4=CC=CC=C4)=C3)C=NC=C1)O

InChi Key:

XSMABFRQESMONQ-SFHVURJKSA-N

PAINs evaluation:

PAINS-Free

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO - d6): 8.36 (s, 1H), 7.82 (d, 1H, J= 5.2 Hz), 7.56 (d, 1H, J = 4.8 Hz), 7.21 - 7.25 (m, 3H), 6.78 - 6.92 (m, 5H), 3.56 - 3.60 (m, 1H), 3.41 - 3.47 (m, 1H), 3.21 (m, 3H), 3.04 - 3.07 (m, 1H), 2.65 - 2.68 (d, 2H, J = 5.6 Hz), 1.77 - 1.84 (m, 3H), 1.64 - 1.68 (m, 1H) .

13 C NMR (400 MHz, DMSO - d 6): 169.5, 149.3, 147.0, 145.3, 138.7, 136.2, 135.7, 131.6, 130.0, 129.5 (2C), 123.8, 121.9, 120.6, 119.8, 119.2 (2C), 115.8, 47.8, 40.5, 36.5, 19.8, 26.2, 19.6.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

35 ± 8 nM

Potency assay:

enzymatic screening assay (AlphaScreen and LANCE)

PDB ID for probe-target interaction (3D structure):

5VGI

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

KDM4B 56 ± 6 nMKDM4D 104 ± 18 nMKDM4A 104 ± 10nM

Probe Selectivity in Vitro:

Enzymatic activity (IC50 nM) KDM2B >4,000; KDM4C 35 ± 8;
KDM3A >4,000; KDM4D 104 ± 18;
KDM3B >4,000; KDM5B 750 ±170;
KDM4A 104 ± 10; KDM6B >4,000;
KDM4B 56 ± 6; PHF8 >4,000

In cell validation

On target activity in cells

Potency in cells:

EC50

3.5 ± 1 (K) nM, 1.3 ±0.3 (H) nM

Potency assay (cells):

Western blot of histone mark; UHPLC–MSMS analysis; cell proliferation methods Assay methods in KYSE-150 (K), H3K36me3 MOA (H), IMR-90 (I) cell lines

Off target activity in cells

Probe Selectivity in Cell:

IMR-90 EC50 >30 uM

In vivo validation

Organism:

female CD-1 mice

Dose:

5 102550 mg/Kg

Route of delivery:

OralIntravenous

Systemic clearance:

6.9 mL/min/kg (IV)

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.7b00220 10.1158/0008-5472.CAN-17-1754

Reference (PMID):

28835804 28883001

Endorsed probe

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

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

The compound represents an important advancement in the field, as it is a potent and selective probe molecule appropriate for both in vitro and in vivo work. Compound shows potent antiproliferative effects at 10 nM in BCS1 cells and even more robust effects at 50 nM in a 3D sphere forming assay. Wonder if recommended dose in cells should be up to 50 nM instead of 100 nM, although given the selectivity profile 100 nM should be ok.

Dec 14 2020 - 8:29am

QC6352 is a chemical probe that inhibits KDM4 family members (KDM4A, KDM4B, KDM4C, and KDM4D) with good specificity within the Jumonji demethylase family. It has been characterised in cancer cell lines as well as organoids derived from breast and colon cancer patients for inhibition of growth. Finally, the drug has been shown to be effective at inhibiting tumour growth in xenograft mouse model of breast cancer through oral dosing. The compound is well tolerated by the mice at doses as high as 50 mg/kg for at least a month. However, no data was provided that showed that inhibition of the tumour growth in vivo was directly tied to the enzymatic activity of the KDM4 family members.

Dec 18 2020 - 10:55am

QC6352

Probe Availability

Probe Information

Target Details

GASC1; JHDM3C; JMJD2C; TDRD14C

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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QC6352

Probe Availability

Probe Information

Target Details

GASC1; JHDM3C; JMJD2C; TDRD14C

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?