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

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

Deadline for manuscript submissions: 30 November 2024 | Viewed by 4247

Special Issue Editor

Prof. Dr. Yujun Zhao

E-Mail Website
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

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Published Papers (4 papers)

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Research

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20 pages, 5978 KiB  
Article
Identification of Novel GANT61 Analogs with Activity in Hedgehog Functional Assays and GLI1-Dependent Cancer Cells
by Dina Abu Rabe, Lhoucine Chdid, David R. Lamson, Christopher P. Laudeman, Michael Tarpley, Naglaa Elsayed, Ginger R. Smith, Weifan Zheng, Maria S. Dixon and Kevin P. Williams
Molecules 2024, 29(13), 3095; https://doi.org/10.3390/molecules29133095 - 28 Jun 2024
Viewed by 888
Abstract
Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at [...] Read more.
Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors. 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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18 pages, 1864 KiB  
Article
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 971
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 [...] Read more.
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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32 pages, 14792 KiB  
Review
Recent Advances in the Application of Nitro(het)aromatic Compounds for Treating and/or Fluorescent Imaging of Tumor Hypoxia
by Kameliya Anichina, Nikolay Lumov, Ventsislav Bakov, Denitsa Yancheva and Nikolai Georgiev
Molecules 2024, 29(15), 3475; https://doi.org/10.3390/molecules29153475 - 25 Jul 2024
Viewed by 743
Abstract
This review delves into recent advancements in the field of nitro(het)aromatic bioreductive agents tailored for hypoxic environments. These compounds are designed to exploit the low-oxygen conditions typically found in solid tumors, making them promising candidates for targeted cancer therapies. Initially, this review focused [...] Read more.
This review delves into recent advancements in the field of nitro(het)aromatic bioreductive agents tailored for hypoxic environments. These compounds are designed to exploit the low-oxygen conditions typically found in solid tumors, making them promising candidates for targeted cancer therapies. Initially, this review focused on their role as gene-directed enzyme prodrugs, which are inert until activated by specific enzymes within tumor cells. Upon activation, these prodrugs undergo chemical transformations that convert them into potent cytotoxic agents, selectively targeting cancerous tissue while sparing healthy cells. Additionally, this review discusses recent developments in prodrug conjugates containing nitro(het)aromatic moieties, designed to activate under low-oxygen conditions within tumors. This approach enhances their efficacy and specificity in cancer treatment. Furthermore, this review covers innovative research on using nitro(het)aromatic compounds as fluorescent probes for imaging hypoxic tumors. These probes enable non-invasive visualization of low-oxygen regions within tumors, providing valuable insights for the diagnosis, treatment planning, and monitoring of therapeutic responses. We hope this review will inspire researchers to design and synthesize improved compounds for selective cancer treatment and early diagnostics. 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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11 pages, 247 KiB  
Review
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 1203
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 [...] Read more.
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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