• 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibition: A Potential Treatment Option for Non-Small Cell Lung Cancer.

      Gargano, Emanuele M; Mohamed, Abdelrahman; Abdelsamie, Ahmed S; Mangiatordi, Giuseppe F; Drzewiecka, Hanna; Jagodziński, Paweł P; Mazzini, Arcangela; van Koppen, Chris J; Laschke, Matthias W; Nicolotti, Orazio; et al. (ACS, 2021-11-18)
      In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17β-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17β-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17β-HSD1 and 1 hold promise in fighting NSCLC.
    • Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.

      Hartman, Alwin M; Elgaher, Walid A M; Hertrich, Nathalie; Andrei, Sebastian A; Ottmann, Christian; Hirsch, Anna K H; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Chemical Society (ACS), 2020-02-28)
      Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Herein, we pioneered the first application of dynamic combinatorial chemistry (DCC) to a PPI target, to find modulators of 14-3-3 proteins. Evaluation of the amplified hits from the DCC experiments for their binding affinity via surface plasmon resonance (SPR), revealed that the low-micromolar (KD 15-16 μM) acylhydrazones are 14-3-3/synaptopodin PPI stabilizers. Thus, DCC appears to be ideally suited for the discovery of not only modulators but even the more elusive stabilizers of notoriously challenging PPIs.
    • Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies.

      Della Volpe, Serena; Nasti, Rita; Queirolo, Michele; Unver, M Yagiz; Jumde, Varsha K; Dömling, Alexander; Vasile, Francesca; Potenza, Donatella; Ambrosio, Francesca Alessandra; Costa, Giosué; et al. (ACS, 2019-01-21)
      The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (i.e., cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex.