In 1954 the German company Chemie Grunenthal synthesized a series of compounds in search of novel antibiotics.  While thalidomide did not have antibiotic properties it seemed to have some interesting sedative effects.  In 1957, the company launched thalidomide as a sedative and after the safe use in nursing mothers, began marketing it for morning sickness.  In 1959, cases of peripheral neuropathy were reported which motivated the FDA to request additional testing before the drug would be allowed in the US.  By 1961 thalidomide was the bestselling sedative in Germany.  However, in the same year, Drs. McBride and Lenz reported the correlation of thalidomide use during pregnancy and the birth defect known as phocomelia.  The drug was then withdrawn from use worldwide but thousands of children were already affected.<br/><br/>In 1992, I hypothesized that drugs with putative anti-angiogenic activity could be identified by screening the literature for compounds known to interfere with female reproductive function.  Angiogenesis is critical to normal menstrual cycles, placental formation and fetal development.  Thus I searched for drugs which had reported side effects of causing both amenorrhea and birth defects.  Thalidomide was known to have these effects and was tested in our animal models of angiogenesis.  We found that racemic thalidomide inhibited growth factor induced angiogenesis in multiple systems, which was enhanced by the use of pure S isomer.   As well, thalidomide analogs which were teratogenic, such as EM12, had anti-angiogenic activity and those analogs that were not teratogenic, such as supidomide, were not anti-angiogenic.  We then showed that thalidomide could suppress the growth of V2 carcinomas in rabbits.  Based upon these findings, thalidomide was tested in humans as an anti-cancer agent.  Further structure activity experiments in our laboratory in 1994 found that the addition of an amino group to the aromatic ring resulted in potent anti-angiogenic and anti-cancer compounds.  As we first reported for amino-thalidomide, these compounds hit two compartments, since they are able to directly inhibit both blood vessels and myeloma cells.  Amino-thalidomide (Pomalyst) and amino-EM12 (Revlimid) are now FDA approved for the treatment of Multiple Myeloma.

Discovery of thalidomide and amino substituted analogs as anticancer agents

249th National Meeting (2015)

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