The concept of "molecular glue" originated in the late 20th century, with immunosuppressants like cyclosporine A (CsA) and FK506 identified as pioneering examples. CsA, discovered in 1971 during routine screening for antifungal antibiotics, exhibited immunosuppressive properties by inhibiting the peptidyl–prolyl isomerase activity of cyclophilin, ultimately preventing organ transplant rejections. By 1979, CsA was used clinically, and FK506 (tacrolimus), discovered in 1987 by Fujisawa, emerged as a more potent immunosuppressant. The ensuing 4-year race to understand CsA and FK506's mechanisms led to the identification of FKBP12 as a common binding partner, marking the birth of the "molecular glue" concept. The term molecular glue found its way into publications in 1992, highlighting the selective gluing of specific proteins by antigenic peptides, akin to immunosuppressants acting as docking assemblies.
In the early 1990s, researchers delved into understanding the role of proximity in biological processes. The creation of synthetic "chemical inducers of proximity" (CIPs), such as FK1012, opened the door to more complex molecular glues. Rimiducid, a purposefully synthesized molecular glue, demonstrated its effectiveness in eliminating graft-versus-host disease by inducing dimerization of death-receptor fusion targets.
The exploration of molecular glues took a significant turn in 1996 with the discovery that discodermolide stabilized the association of alpha and beta tubulin monomers, functioning as a "molecular clamp" rather than inducing neo-associations. In 2000, the revelation that a synthetic compound, synstab-A, could induce associations of native proteins marked a shift towards the discovery of non-natural molecular glues.
In 2013, the mechanism of thalidomide analogs as molecular glue degraders had been explained. Notably, thalidomide, discovered as a CRBN ligand in 2010, and lenalidomide formed a complex with CK1α, solidifying their role as molecular glues. Subsequently, indisulam was identified as a molecular glue capable of degrading RBM39 in 2017.
The year 2020 saw the discovery of autophagic molecular degraders and the identification of BI-3802 as a molecular glue inducing the polymerization and degradation of BCL6. Additionally, chemogenomic screening revealed structurally diverse molecular glue degraders targeting cyclin K. The discovery that manumycin polyketides acted as molecular glues, fostering interactions between UBR7 and P53, further expanded the understanding of molecular glue functions.
In recent years, the field of molecular glues has witnessed an explosion of discoveries targeting native proteins. Examples include synthetic FKBP12-binding glues like FKBP12-rapadocin, which targets the adenosine transporter SLC29A1. Thalidomide and lenalidomide, classified as immunomodulatory drugs (IMiDs), were identified as small-molecule glues inducing ubiquitination of transcription factors via E3 ligase complexes. Computational searches for molecular-glue degraders in 2020 added novel probes to the ever-expanding landscape of molecular glues.
The transformative power of molecular glues in medicine became evident as drugs like sandimmune, tacrolimus, sirolimus, thalidomide, lenalidomide, and taxotere proved effective. The concept of inducing protein associations has shown promise in gene therapy and has become a potent tool in understanding cell circuitry. As the field continues to advance, the discovery of new molecular glues offers the potential to reshape drug discovery and overcome previously labeled "undruggable" targets. The future of molecular glues holds promise for rewiring cellular circuitry and providing innovative solutions in precision medicine.