Tecnologia PROTAC baseada na p53 mutante para o desenvolvimento de fármacos anticancerígenos

Cancers carrying TP53 mutations are often associated with poorer prognosis and increased resistance to standard treatments. Recognizing the urgent need for more effective interventions, the main goal of PROTAC4OncoP53 is the development of a novel strategy to specifically degrade mutant p53 using PROTACs. This approach not only circumvents the resistance often encountered with mutant p53 reactivators but also addresses the potential off-target effects associated with traditional anti-cancer drugs. PROTACs can be designed with a high degree of specificity for mutant p53, minimizing impact on normal, healthy cells. The project is based on the expertise of team members and preliminary data of the team. Taking advantage of the PI group ́s experience in developing p53 activators (see PI’s CV), the team will develop PROTACs based on mutant p53 ligands previously identified by the team. Moreover, the team has already successfully synthesized PROTACs for CREBBP degradation and has experience preparing E3 ligase ligands to be used in this project. In PROTAC4OncoP53 project, the team intends to successfully develop two different series of novel PROTACs targeting mutant p53. We have already a new series of mutant p53 ligands in hand that will be used to develop new PROTACs. These mutp53 ligands will be connected to different E3 ligase recruiters, recognised by CRBN and von Hippel-Lindau (VHL) ligases, via variable-length linkers. Moreover, we will develop PROTACs connected to a MDM2 ligand previously identified by the team. The objectives of PROTAC4OncoP53, very ambitious and beyond the state of the art, are: - Introduce innovative chemical designs and synthesis strategies, pushing beyond the state of the art in PROTAC technology and in mutant p53 modulators. - Determine binding affinities (Kd values) for ligands and final PROTACs, offering a detailed understanding of the molecular interactions critical for efficient target degradation. - Validate the efficacy of PROTACs in inducing target protein degradation, addressing the challenge of targeted mut p53 elimination. - Evaluate the anti-proliferative effects of developed PROTACs in cancer cells while minimizing impact on normal cells, addressing the challenge of specificity and potential side effects. - Explore apoptosis and cell cycle arrest mechanisms induced by PROTACs, advancing the understanding of their mode of action beyond mere degradation. - Investigate the synergistic potential of the best PROTACs with existing anticancer drugs with different mechanisms of action, aiming to enhance therapeutic efficacy and overcome challenges related to single-agent resistance. By integrating findings from all tasks, the team will establish a comprehensive understanding of mut p53 PROTACs and establish the potential of developed PROTACs as candidates for further preclinical and clinical studies for cancers expressing mutant forms of p53. Moreover, this project will foster interdisciplinary collaboration (national and international), promoting innovation and breakthroughs in cancer therapeutics. The results will be presented in scientific meetings and published in high-impact journals. By addressing all these objectives, the PROTAC4OncoP53 project aims to significantly contribute to the field of targeted cancer therapy, surpassing existing knowledge and paving the way for the development of next-generation anticancer molecules with improved efficacy and specificity.