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PROTAC T3   Click here for help

GtoPdb Ligand ID: 13175

Compound class: Synthetic organic
Comment: T3 is a PROTAC degrader that simultaneously targets alpha-synuclein (α-Syn) and tau proteins [1]. It was developed for potential to reduce pathological α-Syn and tau aggregations for application as a neurodegenerative disease therapy. The target protein warhead binds both α-Syn and tau, and the cereblon E3 ubiquitin ligase is engaged by a pomalidomide moiety.
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 14
Hydrogen bond donors 3
Rotatable bonds 19
Topological polar surface area 199.26
Molecular weight 729.8
XLogP -0.83
No. Lipinski's rules broken 3

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CC1=CC=C2C(=C1)SC(=N2)C3=CC=C(C=C3)NCCOCCOCCOCCNC(=O)COC4=C5C(=CC=C4)C(=O)N(C6CCC(=O)NC6=O)C5=O
Isomeric SMILES CC=1C=CC2=C(C1)SC(=N2)C=3C=CC(=CC3)NCCOCCOCCOCCNC(COC4=C5C(N(C(C5=CC=C4)=O)C6CCC(NC6=O)=O)=O)=O
InChI InChI=1S/C37H39N5O9S/c1-23-5-10-27-30(21-23)52-35(40-27)24-6-8-25(9-7-24)38-13-15-48-17-19-50-20-18-49-16-14-39-32(44)22-51-29-4-2-3-26-33(29)37(47)42(36(26)46)28-11-12-31(43)41-34(28)45/h2-10,21,28,38H,11-20,22H2,1H3,(H,39,44)(H,41,43,45)
InChI Key PWVHWGSXBYTNNZ-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
T3 binding affinity (Kd) for α-Syn is 470 nM [1]. The DC50 for T3-induced α-Syn degradation is 1.57 μM, and for tau degradation the DC50 is 4 μM. T3 crosses the blood-brain barrier in vivo, and promotes the clearance of α-Syn and tau from the brains of MPTP-induced Parkinson's disease model mice. T3 binding affinity (Kd) for α-Syn is 470 nM.
Selectivity at ligand targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
microtubule associated protein tau Hs None Binding 5.6 pKd -
⤷ pKd 5.6 (Kd 2.78x10-6 M)