New Drug Discovery Approaches to target undruggable oncogenic targets
[eng] Modern drug discovery has focused on developing selective small molecules that bind enzymatic active sites to modulate protein function. However, over 80% of human proteins remain "undruggable" due to their lack of defined binding pockets and dynamic and / or unstructured surfaces. T...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:dnet:ubarcelona__::2851ed4fcf7212a1e9af47a7a779b5bd |
| Acceso en línea: | https://hdl.handle.net/2445/228743 https://hdl.handle.net/10803/697201 |
| Access Level: | acceso abierto |
| Palabra clave: | Química farmacèutica Desenvolupament de medicaments Oncogens Proteïnes Proteòmica Pharmaceutical chemistry Drug development Oncogenes Proteins Proteomics |
| Sumario: | [eng] Modern drug discovery has focused on developing selective small molecules that bind enzymatic active sites to modulate protein function. However, over 80% of human proteins remain "undruggable" due to their lack of defined binding pockets and dynamic and / or unstructured surfaces. This PhD thesis addresses this gap by exploring innovative chemical strategies to target undruggable cancer-related proteins, focusing on cMyc, Cyclin E / CDK2, and Brd4, which indirectly affect cMyc. The first objective targets the undruggable cMyc using PROTAC technology. Two generations of PROTACs were developed: the first, based on 10058-F4 derivatives and PEG linkers, showed limited degradation efficacy. In contrast, the second generation, incorporating 28RH ligand and alkyl linkers, significantly improved degradation efficiency. Among these, ASA_MDEG-542 demonstrated potent, dose-dependent cMyc degradation, highlighting the critical role of linker design and providing a foundation for further development of cMyc degraders. The second objective addresses Cyclin E, another elusive oncogenic driver, through a "bridged PROTAC" strategy that hijacks its natural partner CDK2 for dual degradation. Six first-generation Cyclin E / CDK2 PROTACs have been synthesized, using ARG-91 as a warhead. Among them, CYC-3 has demonstrated the most promising CDK2 degradation, providing proof-of-concept for this indirect degradation strategy and setting the stage for further optimization with higher-affinity ligands like ARG-15. The final chapter explores a FBDD to develop novel inhibitors targeting Brd4(BD1), a key epigenetic regulator. Using an automated fragment evolution platform and the NAOMInext computational tool, the SSR4 scaffold has been identified and evolved into potent derivatives. Despite synthetic challenges, the optimized compound SSR12 achieved a 650-fold improvement in affinity compared to the original fragment, reaching potency comparable to (+)-JQ1. Overall, this thesis presents innovative methodologies to expand the druggable proteome, offering new therapeutic strategies against cancers driven by undruggable targets through the combined use of PROTAC technology, computational drug design, and fragment-based discovery. |
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