2020 年 78 巻 5 号 p. 414-420
The molecular glue that connects two different proteins is a unique but not an entirely new chemical entity. One of the notable research achievements with this molecular class is sequential identification of molecular mechanisms of two immunosuppressive natural products FK506 and rapamycin. FK506 binds to FKBP12 to interact with and inhibit the protein phosphatase calcineurin. Likewise, rapamycin binds to FKBP12 to interact with and inhibit the phosphatidylinositol 3-kinase-related kinase mTOR. Importantly, the molecular glue story has recently been extended to synthetic small molecule space as well. Clinically important myeloma drug lenalidomide and other immunomodulatory imide drugs (IMiDs) were found to hijack the cullin 4 (CUL4)-RING E3 ubiquitin ligase system by binding to the one of DDB1- and CUL4-associated proteins (DCAFs), cereblon (CRBN), to redirect the substrate selectivity of CRBN. In consequence of the small molecule mediated neo-substrate recruitment, IMiDs induce the proteasomal degradation of the transcription factors IKZF1, IKZF3 and casein kinase 1α in a selective manner. We also reported that a series of anticancer sulfonamides such as E7070 (indisulam) and E7820 induce the protein-protein interaction between another DCAF protein DCAF15 and the slicing factor CAPERα (also known asRBM39), resulting in the selective proteaosomal degradation of CAPERα as a neo-substrate for the E3 ubiquitin ligase. All these findings may indicate a significant opportunity to gain a new insight into molecular glues in drug discovery, leading to further development of new modalities of bi-functional selective protein degraders with target protein knockdown function, represented by PROTAC (Proteolysis Targeting Chimera), Degronimide, and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser).