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Small-Molecule Modulators Targeting Emerging Therapeutic Pathways: Design, Synthesis and Biological Evaluation

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Special Issue Editor

Prof. Dr. Yujun Zhao

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Guest Editor

State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Interests: protein–protein interaction; small-molecule inhibitors; kinase inhibitors; molecular glues; immunomodulators; anticancer therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the post-genomic era, the therapeutic modalities of human diseases have evolved dramatically. Small-molecule modulators used to be the standard option for defined therapeutic pathways; however, antibodies, nucleotide-based drugs, and cell-based therapies are attracting increasing amounts of attention. Many novel therapeutic targets are emerging driven by advancements in biologic and clinical research, providing new opportunities for small-molecule modulators. For example, the inhibition of cellular protein–protein interactions was once considered undruggable but has now been proven to be workable in light of Venetoclax. In addition, specific cellular protein(s) can now be selectively degraded in the presence of rationally designed PROTACs and/or molecular glues, while small-molecule modulators of human immunity also show great therapeutic promises in human clinical trials. Notwithstanding, small-molecule modulators of enzymes are still a fruitful area of research delivering numerous marketed drugs. One notable example is that more than 70 small-molecule inhibitors of kinases have been approved by the FDA and hundreds of clinical trials are ongoing, testing more novel ones. In view of the dynamic evolution of small-molecule modulators targeting emerging therapeutic pathways, this Special Issue welcomes original research concerning their design, synthesis and biological evaluation

Prof. Dr. Yujun Zhao
Guest Editor

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Keywords

immunomodulator
enzymatic modulator
PROTAC
molecular glue
modulator of PPI
receptor agonist
receptor antagonist
small molecules

Published Papers (2 papers)

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Research

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18 pages, 1864 KiB

Open AccessArticle

Sterol Derivatives Specifically Increase Anti-Inflammatory Oxylipin Formation in M2-like Macrophages by LXR-Mediated Induction of 15-LOX

by Reiichi Ohno, Malwina Mainka, Rebecca Kirchhoff, Nicole M. Hartung and Nils Helge Schebb

Molecules 2024, 29(8), 1745; https://doi.org/10.3390/molecules29081745 - 12 Apr 2024

Viewed by 532

Abstract

The understanding of the role of LXR in the regulation of macrophages during inflammation is emerging. Here, we show that LXR agonist T09 specifically increases 15-LOX abundance in primary human M2 macrophages. In time- and dose-dependent incubations with T09, an increase of 3-fold for ALOX15 and up to 15-fold for 15-LOX-derived oxylipins was observed. In addition, LXR activation has no or moderate effects on the abundance of macrophage marker proteins such as TLR2, TLR4, PPARγ, and IL-1RII, as well as surface markers (CD14, CD86, and CD163). Stimulation of M2-like macrophages with FXR and RXR agonists leads to moderate ALOX15 induction, probably due to side activity on LXR. Finally, desmosterol, 24(S),25-Ep cholesterol and 22(R)-OH cholesterol were identified as potent endogenous LXR ligands leading to an ALOX15 induction. LXR-mediated ALOX15 regulation is a new link between the two lipid mediator classes sterols, and oxylipins, possibly being an important tool in inflammatory regulation through anti-inflammatory oxylipins. Full article

(This article belongs to the Special Issue Small-Molecule Modulators Targeting Emerging Therapeutic Pathways: Design, Synthesis and Biological Evaluation)

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Review

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11 pages, 247 KiB

Open AccessReview

Targeting Moonlighting Enzymes in Cancer

by Chunxu Lin, Mingyang Yu, Ximei Wu, Hui Wang, Min Wei and Luyong Zhang

Molecules 2024, 29(7), 1573; https://doi.org/10.3390/molecules29071573 - 1 Apr 2024

Viewed by 651

Abstract

Moonlighting enzymes are multifunctional proteins that perform multiple functions beyond their primary role as catalytic enzymes. Extensive research and clinical practice have demonstrated their pivotal roles in the development and progression of cancer, making them promising targets for drug development. This article delves into multiple notable moonlighting enzymes, including GSK-3, GAPDH, and ENO1, and with a particular emphasis on an enigmatic phosphatase, PTP4A3. We scrutinize their distinct roles in cancer and the mechanisms that dictate their ability to switch roles. Lastly, we discuss the potential of an innovative approach to develop drugs targeting these moonlighting enzymes: target protein degradation. This strategy holds promise for effectively tackling moonlighting enzymes in the context of cancer therapy. Full article

(This article belongs to the Special Issue Small-Molecule Modulators Targeting Emerging Therapeutic Pathways: Design, Synthesis and Biological Evaluation)

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