CC-90009

Protein target name:

GSPT1

Mechanism of action:

Molecular Glue, Degrader

Recommended Concentration for use in cells:

100 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Subclass:

Translation Termination Factor

HUGO ID:

HGNC:4621

Entrez gene ID:

2935

UNIPROT ID:

P15170

Target alias:

551G9.2, ETF3A, GST1, eRF3a

Probe Details

Chemical Probes Portal ID:

CPP2273

Probe alias:

Cereblon modulator 1, cpd 16, V4M

PubChem CID:

118647211

SMILES string:

O=C(NCC1=CC2=C(C(N(C(CC3)C(NC3=O)=O)C2)=O)C=C1)C(F)(F)C4=CC=C(Cl)C=C4

InChi Key:

PWBHUSLMHZLGRN-UHFFFAOYSA-N

Orthogonal probe:

MG-277

Physico-chemical properties

NMR:

1H NMR (500 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 9.68 (t, J = 6.15 Hz, 1H), 7.69 (d, J = 7.88 Hz, 1H), 7.58–7.66 (m, 4H), 7.33–7.44 (m, 2H), 5.11 (dd, J = 13.24, 5.04 Hz, 1H), 4.39–4.50 (m, 3H), 4.24–4.35 (m, 1H), 2.85–2.98 (m, 1H), 2.61 (dd, J = 15.29, 2.05 Hz, 1H), 2.39 (dd, J = 12.93, 4.73 Hz, 1H), 1.95–2.07 (m, 1H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

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

6XK9

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

Proteomics: Proteomic experiments with concentration range from 0.20 μM up to 3 μM with 4 or 6 h incubation shows GSPT1 is the only detectable protein degraded with greater than ∼75% degradation.

Ouside Target Family: Selective in its degradation over other proteins (IKZF1/3 EC50 > 10 μM). CC-90009 (up to 3 μM) did not inhibit P-gp, BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MATE2-K. CC-90009 was screened against a diverse panel of 255 kinases at 3 μM with no inhibition observed >20%. The selectivity of CC-90009 was explored against 80 different human receptors, ion channels, and transporters, and at a concentration of 10 μM, CC-90009 inhibited receptor binding ≥50% at only two receptors, M1(h) and M2(h).

In cell validation

On target activity in cells

Potency in cells:

DC50, Dmax

9 nM, 51% @ 4h 88% @ 20, 44 nM (IC50)

Potency assay (cells):

ePL Degradation Assay (ePL tagged GSPT1), Cell Proliferation assay, Cell Apoptosis assay Phenotypic

Phenotypic Control Experiment:

GSPT1 degradation can be rescued with cotreatment of proteasome inhibitor MG132, bortezomib or the neddylation inhibitor MLN4924.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

not cytotoxic for epithelial cells (THLE-2 IC50 >10 uM)

In vivo validation

Organism:

Mouse, Rat, Cyno

Dose:

1-2 mg/Kg

Route of delivery:

Intravenous

Systemic clearance:

67.9 (M), 28.3 (R), 6 (C) mL/min/kg

Vss:

1 (M), 2.2 (R), 1.2 (C) L/Kg

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.0c01489 10.1182/blood.2020008676

Reference (PMID):

33591756 33197925

CC-90009

Probe Availability

Probe Information

Target Details

551G9.2, ETF3A, GST1, eRF3a

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

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CC-90009

Probe Availability

Probe Information

Target Details

551G9.2, ETF3A, GST1, eRF3a

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?