Cancer Therapy through Death Receptor induced Apoptosis - CaTheDRA
| Reference number | |
| Coordinator | Göteborgs universitet - Institutionen för kemi och molekylärbiologi |
| Funding from Vinnova | SEK 2 038 560 |
| Project duration | September 2019 - August 2021 |
| Status | Completed |
Important results from the project
We have aimed to explore key protein-protein interactions (PPIs) of importance in tumor development and in the defense machinery of cancer cells, and to identify small molecules and peptidomimetic compounds capable of modulating these interactions. We will pay special attention to PPIs during the equilibrium phase of tumor immunoediting processes which lead to significant suppression of natural Death Receptor (DR)-induced apoptosis.
Expected long term effects
Identification of the key PP interactions during the DISC formation and mechanism of binding of each DISC component (Death-receptor, FADD, Caspase8, and cFLIP), provide us unique information regarding the development/design of small molecules and/or peptidomimetics capable of selectively inhibit the cFLIP recruitment at the DISC without blocking recruitment of procaspase-8 to retrigger extrinsic apoptosis signaling pathways in tumor cells.
Approach and implementation
We used five of the most employed proteinprotein docking engines, HADDOCK, ClusPro, HDOCK, GRAMM-X, and ZDOCK, in order to improve the accuracy of the predicted docking complexes. MD simulations, Metadynamics, molecular docking, residue scanning, and clustering calculations were done using Schrodinger software suite. In addition, a series of in-cellulo protein-fragment complementation assays were conducted to validate the proteinprotein docking procedure. The potential cFLIP inhibitors were tested using in cellulo protein-fragment complementation assay (PCA).