Thalidomide’s history is one of the darkest in pharmaceutical history. Today, Thalidomide is still used in the treatment of leprosy and multiple myeloma. Till date Thalidomide’s exact mode of action, essential to its efficacy is unclear and research in the last decade has led to the proposal of 16 possible mechanisms. Details of Thalidomide’s molecular mechanism and its molecular targets can help to reveal analogues lacking the teratogenic effects. This report will particularly focus on some of the recent studies into Thalidomide’s teratogenic mode of action on malignant MM cells; specifically its mode of action on cereblon (CRBN) in MM.

Results
Studies have revealed that Thalidomide directly binds with CRBN, a protein that forms a complex …show more content…
This Thalidomide binding region (TBR) is very conserved amongst species except rats as the TBR varies by four amino acids – a likely explanation for why rats were not responsive to Thalidomide. Despite this, studies show that CRBN has similar binding affinities to Thalidomide analogues; Pomalidomide and Lenalidomide[ ]. Elution studies show that CRBN binds only to the glutamiride part of these analogues and not the phthalimide part. It is common knowledge that these FDA approved analogues have significantly less side-effects than the pioneer drug and accordingly questions why a Thalidomide derivative can’t be prescribed …show more content…
Thalidomide (50mg) or Bortezomib (50mg) was administered daily to patients daily for two years. The patients underwent gene expression profiling prior to the trial. Results from both trials showed that elevated CRBN gene expression was significantly associated with longer progression-free survival (P = 0.005). On the other hand, no association was found between CRBN expression and Bortezomib maintenance [3]. Although patients were randomised in this trial, there was no information to state whether the patients were tested for resistance to either Thalidomide or Bortezomib prior to the study. This is important as if any patients are resistant to any either drug, the results will be skewed using Bortezomib as a control will be useless. An improvement would be to administer a pharmacologically inactive placebo drug so that the efficacy of Thalidomide will be distinct. That being said, this report has discussed corresponding evidence linking CRBN expression to Thalidomide sensitivity so it could be argued that these findings provide further evidence for Thalidomide’s direct anti-MM