thalidomide   Click here for help

GtoPdb Ligand ID: 7327

Synonyms: K-17
Approved drug Immunopharmacology Ligand
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.

SARS-CoV-2 and COVID-19: 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).
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
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
Click here for help
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
No information available.
Summary of Clinical Use Click here for help
Thalidomide was originally used treat nausea and alleviate morning sickness in pregnant women. Unfortunately the drug was found to be a powerful human teratogen, causing severe embryopathy, principally malformation of the limbs (phocomelia). This drug has undergone a remarkable metamorphosis, with thalidomide now being repurposed as a treatment for certain cancers (eg multiple myeloma, in combination with dexamethasone, or melphalan and prednisone) and for erythema nodosum leprosum (ENL), a complication of leprosy. As a condition of drug approval, authorising agencies stipulate that female patients with childbearing potential, requiring thalidomide treatment, be advised to use multiple forms of contraception and/or be counselled and educated regarding the risks associated with taking the drug, and the importance of avoiding pregnancy. They may also be offered regular pregnancy tests.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
As an antineoplastic agent, thalidomide appears to inhibit the angiogenesis essential for tumour growth. Anti-inflammatory action may be due to supression of production of pro-inflammatory cytokines and enhanced production of anti-inflammatory cytokines such as IL-10 [5]. The primary target of thalidomide is the cereblon protein (CRBM, Q96SW2) [4,6], which has been linked to the teratogenic activity of the thalidomide-like drugs [1-2]. Cereblon has multiple actions, including participation in protein ubiquitination complexes and regulation of potassium channels [1,3].
External links Click here for help