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Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 11642

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Special Issue Editors

Prof. Dr. Stefania Villa

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Guest Editor

Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133 Milano, Italy
Interests: medicinal chemistry; design and synthesis of anticancer and antitubercular agents; QSAR

Prof. Dr. Arianna Gelain

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Guest Editor

University of Milan, Department of Pharmaceutical Sciences, via L. Mangiagalli 25, 20133 Milano, Italy
Interests: medicinal chemistry; design and synthesis of anticancer and antimicrobic agents; QSAR

Special Issue Information

Dear Colleagues,

We are pleased to announce that submissions for the Molecules Special Issue “Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways” are now being accepted.

Signaling pathways play a key role in the modulation of cellular activity. They are considered to be a rich source of target candidates, since the abnormal activation of these physiological pathways may cause several pathological conditions, including cancer, autoimmune diseases, and diabetes. This Special Issue will focus on the recent advances in medicinal chemistry concerning drug discovery, the development of new small molecules targeting signaling pathways, and their possible therapeutic applications.

We welcome original research articles as well as perspective papers and reviews.

Prof. Dr. Stefania Villa
Prof. Dr. Arianna Gelain
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

small molecules
natural compounds
synthetic compounds
signaling pathways
drug design
drug development
HTS
computational tools
biological evaluations
QSAR
bioavailability
pharmacokinetics
regulatory issues

Published Papers (5 papers)

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Research

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16 pages, 5280 KiB

Open AccessArticle

Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model

by Sena Kim, Peter Ruminski, Megh Singh, Karl Staser, Kidist Ashami, Julie Ritchey, Sora Lim, John F. DiPersio and Jaebok Choi

Molecules 2024, 29(8), 1801; https://doi.org/10.3390/molecules29081801 - 16 Apr 2024

Viewed by 529

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib. Full article

(This article belongs to the Special Issue Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways)

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15 pages, 2421 KiB

Open AccessArticle

Effects of the Calix[4]arene Derivative Compound OTX008 on High Glucose-Stimulated ARPE-19 Cells: Focus on Galectin-1/TGF-β/EMT Pathway

by Maria Consiglia Trotta, Francesco Petrillo, Carlo Gesualdo, Settimio Rossi, Alberto Della Corte, Judit Váradi, Ferenc Fenyvesi, Michele D’Amico and Anca Hermenean

Molecules 2022, 27(15), 4785; https://doi.org/10.3390/molecules27154785 - 26 Jul 2022

Cited by 6 | Viewed by 1800

Abstract

Diabetic retinopathy (DR) is a neurovascular disease characterized by the reduction of retina integrity and functionality, as a consequence of retinal pigment epithelial cell fibrosis. Although galectin-1 (a glycan-binding protein) has been associated with dysregulated retinal angiogenesis, no evidence has been reported about galectin-1 roles in DR-induced fibrosis. ARPE-19 cells were cultured in normal (5 mM) or high glucose (35 mM) for 3 days, then exposed to the selective galectin-1 inhibitor OTX008 (2.5–5–10 μM) for 6 days. The determination of cell viability and ROS content along with the analysis of specific proteins (by immunocytochemistry, Western blotting, and ELISA) or mRNAs (by real time-PCR) were performed. OTX008 5 μM and 10 μM improved cell viability and markedly reduced galectin-1 protein expression in cells exposed to high glucose. This was paralleled by a down-regulation of the TGF-β/, NF-kB p65 levels, and ROS content. Moreover, epithelial–mesenchymal transition markers were reduced by OTX008 5 μM and 10 μM. The inhibition of galectin-1 by OTX008 in DR may preserve retinal pigment epithelial cell integrity and functionality by reducing their pro-fibrotic phenotype and epithelial–mesenchymal transition phenomenon induced by diabetes. Full article

(This article belongs to the Special Issue Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways)

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18 pages, 2204 KiB

Open AccessArticle

Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

by Serhii A. Liakhov, Igor A. Schepetkin, Olexander S. Karpenko, Hanna I. Duma, Nadiia M. Haidarzhy, Liliya N. Kirpotina, Anastasia R. Kovrizhina, Andrei I. Khlebnikov, Irina Y. Bagryanskaya and Mark T. Quinn

Molecules 2021, 26(18), 5688; https://doi.org/10.3390/molecules26185688 - 20 Sep 2021

Cited by 11 | Viewed by 2840

Abstract

c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs. Full article

(This article belongs to the Special Issue Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways)

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Review

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14 pages, 1389 KiB

Open AccessReview

Immunoregulatory Role of the Mechanosensitive Ion Channel Piezo1 in Inflammation and Cancer

by Yuexin Wang, Zhiyuan Zhang, Qiuli Yang, Yejin Cao, Yingjie Dong, Yujing Bi and Guangwei Liu

Molecules 2023, 28(1), 213; https://doi.org/10.3390/molecules28010213 - 26 Dec 2022

Cited by 4 | Viewed by 3258

Abstract

Piezo1 was originally identified as a mechanically activated, nonselective cation ion channel, with significant permeability to calcium ions, is evolutionally conserved, and is involved in the proliferation and development of various types of cells, in the context of various types of mechanical or innate stimuli. Recently, our study and work by others have reported that Piezo1 from all kinds of immune cells is involved in regulating many diseases, including infectious inflammation and cancer. This review summarizes the recent progress made in understanding the immunoregulatory role and mechanisms of the mechanical receptor Piezo1 in inflammation and cancer and provides new insight into the biological significance of Piezo1 in regulating immunity and tumors. Full article

(This article belongs to the Special Issue Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways)

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17 pages, 3366 KiB

Open AccessReview

Insights on the Modulation of SIRT5 Activity: A Challenging Balance

by Matteo Mori, Giulia Cazzaniga, Fiorella Meneghetti, Stefania Villa and Arianna Gelain

Molecules 2022, 27(14), 4449; https://doi.org/10.3390/molecules27144449 - 12 Jul 2022

Cited by 6 | Viewed by 1993

Abstract

SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field. Full article

(This article belongs to the Special Issue Recent Advances in Small-Molecule Therapeutics Targeting Signaling Pathways)

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