thalidomide   

GtoPdb Ligand ID: 7327

Synonyms: K-17
thalidomide is an approved drug (FDA (1998), EMA (2008))
Compound class: Synthetic organic
Comment: Thalidomide is principally an immunomodulatory drug. It inhibits synthesis of TNFα. Mechanistically, thalidomide binds to cereblon, and this complex recruits substrate proteins for degradation by the ubiquitin system. The lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) have been identified as substrates for thalidomide-bound cereblon. More recently another transcription factor, PLZF (ZBTB16), has been reported as a potential thalidomide/cereblon substrate [7]. Knockdown of Plfz induces skeletal abnormalities in chicken limbs, so thalidomide-targeted degradation of PLZF would be predicted to exhibit similar teratogenic effects.

COVID-19/SARS-CoV-2
Thalidomide + low-dose glucocorticoid is being evaluated for efficacy in severe COVID-19 pneumonia (preprint available here https://www.preprints.org/manuscript/202002.0395/v1). An alternative approach is examining the combination of thalidomide + celecoxib (which targets NF-κB to suppress production of inflammatory cytokines; see preprint DOI: 10.13140/RG.2.2.26979.91689).
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 1
Topological polar surface area 87.04
Molecular weight 258.06
XLogP 0.92
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES OC1=NC(=O)C(CC1)N1C(=O)c2c(C1=O)cccc2
Isomeric SMILES OC1=NC(=O)C(CC1)N1C(=O)c2c(C1=O)cccc2
InChI InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
InChI Key UEJJHQNACJXSKW-UHFFFAOYSA-N
Classification
Compound class Synthetic organic
Ligand families/groups PROTACs and molecular glues
Approved drug? Yes (FDA (1998), EMA (2008))
WHO Essential Medicine WHO Model List of Essential Medicines (21st List, 2019). Access PDF version.
IUPAC Name
2-(6-hydroxy-2-oxo-2,3,4,5-tetrahydropyridin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
International Nonproprietary Names
INN number INN
762 thalidomide
Synonyms
K-17
Comments
Thalidomide is principally an immunomodulatory drug. It inhibits synthesis of TNFα. Mechanistically, thalidomide binds to cereblon, and this complex recruits substrate proteins for degradation by the ubiquitin system. The lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) have been identified as substrates for thalidomide-bound cereblon. More recently another transcription factor, PLZF (ZBTB16), has been reported as a potential thalidomide/cereblon substrate [7]. Knockdown of Plfz induces skeletal abnormalities in chicken limbs, so thalidomide-targeted degradation of PLZF would be predicted to exhibit similar teratogenic effects.

COVID-19/SARS-CoV-2
Thalidomide + low-dose glucocorticoid is being evaluated for efficacy in severe COVID-19 pneumonia (preprint available here https://www.preprints.org/manuscript/202002.0395/v1). An alternative approach is examining the combination of thalidomide + celecoxib (which targets NF-κB to suppress production of inflammatory cytokines; see preprint DOI: 10.13140/RG.2.2.26979.91689).
Database Links
CAS Registry No. 50-35-1
ChEMBL Ligand CHEMBL468
DrugBank Ligand DB01041
DrugCentral Ligand 2616
GtoPdb PubChem SID 178103899
Immunopaedia Search thalidomide
PubChem CID 5426
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Wikipedia Thalidomide

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Thalidomide
Cat. No. 0652