SD-36

Protein target name:

STAT3

Mechanism of action:

DegraderPROTAC

Recommended Concentration for use in cells:

~~5 nM up to 5 uM~~

Reviewer suggested Concentration for use in cells:

100 nM up to 5 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Transcription factor

Subclass:

Signal transducer and transcription activator

HUGO ID:

HGNC:11364

Entrez gene ID:

6774

UNIPROT ID:

P40763

Target alias:

APRF; HIES; ADMIO; ADMIO1

Probe Details

Chemical Probes Portal ID:

CPP1868

Probe alias:

SD36, STAT3 Degrader 36, PROTAC

PubChem CID:

139600321

SMILES string:

O=C([C@@H](NC([C@@H]1CC[C@H](CCN(C(CCCCCC#CC2=CC=CC3=C2CN(C4CCC(NC4=O)=O)C3=O)=O)C[C@@H]5NC(C6=CC(C=C(C(F)(P(O)(O)=O)F)C=C7)=C7N6)=O)N1C5=O)=O)CCC(N)=O)NC(C8=CC=CC=C8)C9=CC=CC=C9

InChi Key:

JKCSCHXVWPSGBG-OPKPGBGESA-N

Control compound:

SD-36Me

Physico-chemical properties

Solubility - preferred solvent:

DMSO

NMR:

1H NMR (400 MHz, CD3CN:D2O = 1:1) d d 7.90-7.85 (m, 1H), 7.73 – 7.59 (m, 1H), 7.56 – 7.36 (m, 4H), 7.35 – 7.05 (m, 11H), 6.06-6.03 (m, 1H), 5.12 – 4.87 (m, 2H), 4.48 – 4.19 (m, 5H), 3.98 – 3.49 (m, 3H), 3.36 – 3.24 (m, 1H), 2.88 – 2.64 (m, 2H), 2.61 – 2.23 (m, 7H), 2.21 – 1.99 (m, 4H), 1.94 – 1.35 (m, 11H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Ki, KD

11 nM (Ki) 44 nM (KD)

Potency assay:

Fluorescence polarization binding assay, biolayer interferometry sensorgrams

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

6NJS

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

IC50

10 nM

Potency assay (cells):

Luciferase reporter assay

Off target activity in cells

Potency assay, off target (cells):

Multiplexed quantitative proteomics analysis

Probe Selectivity in Cell:

>5000 proteins tested and no observed degradation in 3 different cell lines

In vivo validation

Organism:

SCID female mice

Dose:

25 mg/Kg50 mg/Kg100 mg/Kg

Route of delivery:

Intravenous

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.9b01530 10.1016/j.ccell.2019.10.002

Reference (PMID):

31747516 31715132

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

SD-36 is a potent and selective degrader for STAT3 and STAT3 mutants and highly recommended as a chemical probe. STAT3 is a transcription factor implicated in various human diseases such as cancer. It has been difficult to drug due to the peptidic nature of ligands that bind to its SH2 domain, as well as the difficulty in achieving adequate selectivity for the STAT3 SH2 domain compared to that of other STAT family members. SD-36 addresses this need, and provides a useful tool for binding and removing STAT3 via proteasomal degradation. It demonstrates > 20-fold selectivity for binding STAT3, and >100-fold selectivity for degrading STAT3 compared to other members of the STAT family. It is also exquisitely selective for STAT3 compared to other proteins outside the STAT family according to proteome-wide selectivity analyses. Lastly, SD-36 can be delivered intravenously into mice and shows sustained degradation even out to 72 hours after dosing. For use in cells, I recommend concentrations in the range of 100nM – 5uM depending on the cell line. For use in mice, I recommend dosing at 25 – 100 mg/kg intravenously.

Nov 4 2020 - 10:52am

Recommend dose-response in cell line of interest and note the (p)STAT3 and CRBN status (by western blot for example). Note: At 10 micromolar the recommended control SD-36Me has an effect on STAT3 dimer similar to that of 5 micromolar of the benchmark inhibitor SI-109.

Nov 11 2020 - 10:54am

SD-36

Probe Availability

Probe Information

Target Details

APRF; HIES; ADMIO; ADMIO1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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SD-36

Probe Availability

Probe Information

Target Details

APRF; HIES; ADMIO; ADMIO1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?