The transmembrane interactome of BCL-2 proteins as a target for antitumoral therapies

Esta tesis se ha realizado gracias a la financiacion para estudiantes predoctorales de la AECC. ; The BCL-2 protein family regulates cell death by apoptosis through a complex network of interactions between its pro- and anti-apoptotic members. Numerous types of tumors exhibit alterations in this protein family, that alter the interaction equilibrium, finally contributing to tumor progression. To carry out their functions, BCL-2 proteins interact with each other both in the cytoplasm and on intracellular membranes. Interaction equilibriums of the cytosolic domains, primarily the BH3 domain (BCL-2 homology domain 3), have been extensively studied and recently proposed as therapeutic targets, leading to drugs currently in clinical trials. However, the interactome of the transmembrane domains and their role in controlling cell death remains poorly explored. MCL1, one of the anti-apoptotic members of this family, exerts its function through interaction with the BH3 domains of other pro-apoptotic proteins such as BAK. Increased MCL1 expression has been reported in 30% of tumors, correlating with poor patient prognosis. Consequently, a family of MCL1 BH3 domain mimetics has been developed in recent years, efficiently inducing tumor cell death. However, these BH3 mimetics have exhibited cardiotoxicity in clinical trials, underscoring the need to identify new therapeutic alternatives. In this regard, our group has demonstrated that MCL1 interacts with the pro-apoptotic protein BOK through the transmembrane domain (Lucendo et al., 2020). The hypothesis of this work argues that this interaction may be modulable, thus opening a new therapeutic avenue in cancer treatment. To validate this hypothesis, we focused on three main objectives: -Identifying new modulators of the interaction between the transmembrane domains (TMD) of MCL1 and BOK. - Understanding the mechanism of action of these new molecules. - Evaluating their toxicity and efficacy in in vitro and in vivo models. In this work, we identified two inhibitors of the ...