Thalidomide: History of Research and Perspectives for Its Medical Use (Review)

Thalidomide was used in the 1950s as a sedative. As a result of its marked teratogenicity, it was removed from the market in the 1960s, but returned to the clinic some 40 years later as an antitumor agent. Thalidomide and its derivatives (IMiD and CELMoD) are currently in active use in the treatment of a number of hematological tumors. Its spectrum of properties includes immunomodulatory, anti-inflammatory, and antiangiogenic effects, and neuroprotective and analgesic potentials have been noted. Thalidomide interacts with a component of the ubiquitin ligase complex (cereblon protein), altering its specificity, which leads to proteasomal degradation of a number of neosubstrates, including transcription factors important for embryonic development (SALL4, p63, and PLZF), some which are key for hematological tumors (Ikaros, Aiolos, CK1 alpha, etc.) and some of which regulate the expression of TNF-alpha mRNA. Discovery of its target contributed to the rapid development of PROTAC technology in the context of seeking a method for intracellular degradation of target proteins. A number of studies addressing the current uses of thalidomide and its analogs are described here.