Molecular glues are promising chemical modalities to expand the druggable proteome in drug discovery (1). They promote and stabilize the formation of ternary complexes by bringing together proteins that have very low or no affinity for each other. These complexes trigger downstream signaling. This was first described in plant science with jasmonate hormone and revealed a multicomponent signaling hub (2).
Targeted Protein Degradation (TPD) is another application of this approach. Protein degraders target the disease-causing protein for destruction, utilising the cell’s machinery to induce degradation. (1, 3, 4)
Our molecular glues platform Y2HChem is adapted from the Yeast Two-Hybrid technology. It benefits from Hybrigenics’ expertise in protein-protein interactions (ULTImate Y2H™) and in drug’s target deconvolution (ULTImate YChemH™). It allows to identify protein-protein interactions that depend on the presence of a small molecule.
ULTImate Y2HChem is derived from our ULTImate Y2H and ULTImate YChemH screening technologies. It is a direct protein interaction fishing method based on the well established yeast two-hybrid (Y2H) technique.
This approach relies on the reconstitution of a functional transcription factor (TF) followed by the expression of a reporter gene in genetically modified yeast cells. Upon interactions, the DNA Binding Domain (DBD) of the TF is brought in close proximity to its Activation Domain (AD). Reconstitution of the functional TF activates the transcription of the HIS3 reporter gene, which allows yeast cells to grow on a selective medium lacking histidine. The DNA of the positive clones is then sequenced and analyzed to identify the protein partners
Within our Y2HChem platform, a protein and a small molecule of interest are screened together against highly complex protein domain libraries prepared from any cell type, tissue or organism. The technique involves 3 components:
For more information on our screening technology and libraries, please refer to our ULTImate Y2H, ULTImate YChemH and ULTImate Libraries pages.
For your project, we provide the list of identified protein partners, the exact experimentally defined interaction domain on each protein and a very informative confidence score. Our excellent scientific project leaders support the interpretations of your results and help you to focus on the most relevant interaction partners for the best outcome of your project.
CONTACT US now to discuss your project with our team.
(1) Che, Y, et al., Inducing protein-protein interactions with molecular glues, Bioorg. Med. Chem. Lett. 2585–2592 (2018) . https://doi.org/10.1016/j.bmcl.2018.04.046
(2) Sheard, L., Tan, X., Mao, H. et al. Jasmonateperception by inositol-phosphate-potentiated COI1–JAZ co-receptor. Nature 468, 400–405 (2010). https://doi.org/10.1038/nature09430
(3) Schapira,et al. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov18, 949–963 (2019). https://doi.org/10.1038/s41573-019-0047-y
(4) Hughes SJ, CiulliA. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays Biochem. 2017;61(5):505-516. https://doi.org/10.1042/EBC20170041
(5) Griffith et al. Crystal Structures of Human Calcineurin and the Human FKBP12-FK506-calcineurin Complex, Cell, (1995) 507-22. https://doi.org/10.1038/378641a0
(6) Sievers, Q. et al., Defining the Human C2H2 Zinc Finger DegromeTargeted by Thalidomide Analogs Through CRBN, Science, 2018. DOI: 10.1126/science.aat0572
(7) Lu J. et al., Hijacking the E3 Ubiquitin LigaseCereblonto Efficiently Target BRD4, Chem Biol. 2015; 22:755–63. https://doi.org/10.1016/j.chembiol.2015.05.009