作者: Bello, Ivana ; Guadagni, Anna ; Brindisi, Margherita ; Barone, Simona ; Pelliccia, Sveva ; Panza, Elisabetta ; Alfano, Antonella Ilenia ; Summa, Vincenzo

Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by the lack in the expression of estrogen and progesterone receptors, and human epidermal growth factor receptors 2. TNBC stands out among other breast cancers subtypes for its high aggressiveness and invasiveness, and for the limited therapeutic options available, which justify the poor survival rates registered for this breast cancer subtype. Compelling new evidence pointed out the role of epigenetic modifications in cancer, prompting tumor cell uncontrolled proliferation, epithelial-to-mesenchymal transition, and metastatic events. In this review we showcase the latest evidence supporting the involvement of histone deacetylase 6 (HDAC6) in cancer pathways strictly related to TNBC subtype, also tracking the latest advancements in the identification of novel HDAC6 inhibitors which showed efficacy in TNBC models, offering insights into the potential of targeting this key epigenetic player as an innovative therapeutic option for the treatment of TNBC.

2024-09-26·JOURNAL OF MEDICINAL CHEMISTRY

Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseases

Article

作者: Iriepa, Isabel ; Solana-Manrique, Cristina ; Mora-Morell, Alba ; Rodrìguez, Ania Canseco ; Samadi, Abdelouahid ; Sanchis, Inmaculada ; Toledano-Pinedo, Mireia ; Więckowska, Anna ; Bautista-Aguilera, Òscar M. ; Wolak, Małgorzata ; Knez, Damijan ; Bojarski, Andrzej J. ; Porro-Pérez, Alicia ; Dong, Min ; Dobrydnev, Alexey V. ; Marco-Contelles, José ; Siwek, Agata ; Doroz-Płonka, Agata ; Romero, Fernando ; Rodríguez-Fernández, M. Mercedes ; Griñán-Ferré, Christian ; Satała, Grzegorz ; Schäker-Hübner, Linda ; Sànchez-Pérez, Ana M ; Gobec, Stanislav ; Godyń, Justyna ; Almendros, Pedro ; Handzlik, Jadwiga ; Paricio, Nuria ; Pérez, Belén ; Bellver-Sanchis, Aina ; Hansen, Finn K. ; Matheu, Ander ; Artetxe-Zurutuza, Aizpea

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC₅₀ = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.

2024-09-01·EXPERT OPINION ON THERAPEUTIC TARGETS

Therapeutic indications for HDAC6 inhibitors in the peripheral and central nervous disorders

Review

作者: Rombouts, Frederik ; van Eyll, Jonathan ; Prior, Robert ; Van Den Bosch, Ludo ; Celanire, Sylvain

INTRODUCTION:

Inhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications.

AREAS COVERED:

This review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors.

EXPERT OPINION:

Based on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.

100 项与 HDAC6 inhibitors(Taipei Medical University) 相关的药物交易

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