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- FOXO transcription factors as therapeutic targets in human diseasesPublication . Orea-Soufi, Alba; Paik, Jihye; Bragança, José; Donlon, Timothy A.; Willcox, Bradley J.; Link, WolfgangForkhead box (FOX)O proteins are transcription factors (TFs) with four members in mammals designated FOXO1, FOXO3, FOXO4, and FOXO6. FOXO TFs play a pivotal role in the cellular adaptation to diverse stress conditions. FOXO proteins act as context-dependent tumor suppressors and their dysregulation has been implicated in several age-related diseases. FOXO3 has been established as a major gene for human longevity. Accordingly, FOXO proteins have emerged as potential targets for the therapeutic development of drugs and geroprotectors. In this review, we provide an overview of the most recent advances in our under-standing of FOXO regulation and function in various pathological conditions. We discuss strategies targeting FOXOs directly or by the modulation of upstream regulators, shedding light on the most promising intervention points. We also reveal the most relevant clinical indications and discuss the potential, trends, and challenges of modulating FOXO activity for therapeutic purposes.
- Chromenone derivatives as CRM1 inhibitors for targeting glioblastomaPublication . Princiotto, Salvatore; Jiménez, Lucía; Domínguez, Lucía; Sequeira, João G. N.; Mourato Paulo, Cristiana Isabel; Orea-Soufi, Alba; da Silva Santos, Bruno Filipe; Dallavalle, Sabrina; Machuqueiro, Miguel; Ferreira, Bibiana; Link, WolfgangGlioblastoma (GBM) is one of the most aggressive and deadly cancers. Due to the complexity and redundancy within signaling networks in GBM, targeted inhibitors of specific pathways have shown only limited success. The nuclear export receptor chromosome region maintenance 1 (CRM1) has recently emerged as a promising therapeutic target, as its inhibition can simultaneously disrupt multiple key oncogenic drivers. Herein, whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors is explored. Several chromenonebased derivatives are synthesized and it is demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure–activity relationship is established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, it is showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal-containing substrates in GBM cells. Several of these compounds exhibit selective cytotoxicity againstGBM cell lines, highlighting their potential as targeted therapies for GBM.