Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4CRBN). When a ligand such as thalidomide binds to CRBN, it recognizes various ‘neosubstrates’ depending on the shape of the ligand. CRL4CRBN binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research.
In the standard model of elementary particle physics neutrinos are massless, and therefore the actuality of finite neutrino mass indicates a theory beyond the standard model. The Sun produces abundant neutrinos due to nuclear fusion reactions. A pioneering experiment in the early '70s detected neutrinos from the Sun, but found that the observed flux was smaller than expected, which was then called the missing solar neutrino problem. Tremendous efforts were made both experimentally and theoretically to solve this problem. In 2001, almost 30 years after the first indication, data from Super-Kamiokande in Japan and SNO in Canada together provided evidence that neutrino oscillation effectively converts the solar (electron) neutrinos to non-electron type neutrinos. Neutrino oscillation can occur only for those neutrinos with finite neutrino mass.