Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

European Journal of Medicinal Chemistry
Simone BerardozziFrancesca Ghirga

Abstract

Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling.

Citations

Apr 17, 2019·Cells·Toshiki Terao, Yosuke Minami
Oct 12, 2019·Cancers·Ludovica Lospinoso SeveriniLucia Di Marcotullio
Feb 20, 2020·Expert Opinion on Therapeutic Patents·Deborah QuaglioMattia Mori
May 10, 2020·Antioxidants·Antonia DiukendjievaIlza Pajeva
Apr 9, 2020·ChemMedChem·Marisa E HomJames K Chen
Sep 30, 2020·Expert Opinion on Therapeutic Targets·Ludovica Lospinoso SeveriniLucia Di Marcotullio
Oct 3, 2020·Expert Opinion on Drug Discovery·Christopher O Dusek, M Kyle Hadden
Aug 14, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bruno CasciaroDeborah Quaglio
Nov 30, 2018·Medicinal Research Reviews·Jitender BariwalRam I Mahato
Jun 18, 2020·Antibiotics·Floriana CappielloFrancesca Ghirga
Dec 11, 2020·Cell Death Discovery·Cinzia CaggianoSusanna Dolci
Apr 4, 2021·Chemistry : a European Journal·Elisa BonandiDaniele Passarella
Apr 16, 2019·Journal of Medicinal Chemistry·Ilya GalperinMatthias Lauth

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Trends in Pharmacological Sciences
Paola InfanteLucia Di Marcotullio
Proceedings of the National Academy of Sciences of the United States of America
Joel M HymanJames K Chen
Bioorganic & Medicinal Chemistry Letters
Francesca GhirgaPaola Infante
Bioorganic & Medicinal Chemistry Letters
Wenfeng LuXiaohu Zhang
© 2022 Meta ULC. All rights reserved