HOXA9 degradome · Deciphering the machinery involved in stability of the transcription factor HOXA9.

Deciphering the machinery involved in stability of the transcription factor HOXA9.

The majority of small molecular drugs work as inhibitors designed for occupancy-based strategies. Drugs are designed to bind to the catalytical pocket of an enzyme and block its activity. However only a fraction of human proteins have catalytical pockets capable of this type of intervention. Molecular glue degraders are small molecular drugs which induce interactions between proteins of interest (POI) with E3 ligases, resulting in the ubiquitination and degradation of the POI by leveraging protein – protein interactions between POI and E3 ligase. My project seeks to identify and characterize novel molecular glue degraders. Drug-induced protein degradation holds promise for future targeted cancer treatments. This may ultimately result better outcomes for cancer patients, relieving an economic burden on the health care system. Conclusions of the action We developed a novel approach for molecular glue identification by correlation of the drug toxicity across multiple cancer cell lines with the expression levels of E3 ligases. This method enabled us to identify a new molecular glue – kinase inhibitor CR8. This approach can be used for newly generated datasets and hopefully will enable the discovery of additional molecular glues. Previously described molecular glue degraders (thalidomide or indisulam analogs) induce interaction between the target and substrate receptor (DCAF). Kinase inhibitor CR8 is the first example of the published molecular glue degrader which induces the interaction between target and substrate adaptor. CR8 also modifies the function of the CDK12, transforming it from the kinase to drug-induced substrate receptor, linking DDB1 to the target for ubiquitination. Finally, cycK does not interact directly with CR8 and it is a primary substrate for degradation. By dissecting and describing the molecular mechanism for BI-3802, which induces BCL6 polymerization, we provide structural frameworks for a rational design for a new generation of BCL6 targeting drugs. BI-3802 is a compound characterized with unique tri-modality, (1) BI-3802 inhibits BCL6 (prevents the interaction between BCL6 and co-repressor BCOR), (2) indices BCL6 polymerization (removes BCL6 from chromatin) and (3) initiates BCL6 degradation (promotes SIAH1 ubiquitination and subsequent proteasome degradation). The unique combination of the modalities determines BI-3802 excellent pharmacology. We described a new drug modality - drug-induced polymerization. Structural characterization for the BI-3802 mechanism paves a potential path to rationally optimized new generation of BCL6 drugs as well as design the therapies to targeting other cancer dependencies by employing targeted polymerization mechanism. In aggregate, projects which lead to the characterization of CR8 and BI-3802 as molecular glues demonstrated that modification of the compound surface-exposed moieties can induce gain-of-function glue properties, which provides rationality to modify the surface-exposed inhibitors to transform it into molecular glues. The surface of the protein is changed upon the introduction of the compounds that bind to the target. Since in every cell there are more than 20.000 different proteins with multiple surfaces, a chemical binder to the target can induce complementary to the protein surface of one of the other expressed proteins. Our work suggests there are more compounds that induce new protein interactions.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз