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Pharmaceuticals
Special Issues
Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents
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Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 December 2025 | Viewed by 1056

Special Issue Editors

Dr. David J. Leaver

E-Mail Website
Guest Editor
1. Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia
2. School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia
Interests: drug discovery; enzyme inhibitors; anticancer agents; sterols
Dr. Li Li

E-Mail Website
Guest Editor
Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia
Interests: biominerals; precision delivery; sustainable release; nano-enzyme; combinational therapies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is known to be one of the leading causes of death worldwide, with approximately 20% of the population being diagnosed with cancer in their lifetime. Cancer costs the world economy trillions of dollars each year; therefore, there is a desperate need for new anticancer drugs with known mechanisms of action to circumnavigate issues pertaining to treatment efficacy and drug resistance. 

Many oncogenic enzyme targets (i.e. KRAS, KATs) have been labelled “undruggable” in the past; however, advances in chemical biology and molecular biology have yielded tools that can drug these “undruggable” targets. One such technology that is rapidly advancing through clinical trials is a class of compounds called PROTACs (PROteolysis-TArgeting Chimeras). The first PROTAC to enter phase III trials was vepdegestrant (ARV-471), which is currently being studied as a potential treatment for patients with ER+/HER2− advanced breast cancer. We anticipate that the approval of PROTACs as anticancer agents is just a matter of time.

The use of antibody–drug conjugates (ADCs) as anticancer agents is rising exponentially. More than ten ADCs have already gained Food and Drug Administration (FDA) approval, and we expect this number to rise significantly in the coming years given the fact that there are hundreds of ADCs currently being investigated in clinical trials. Despite the numerous challenges faced by those that develop anticancer therapeutics, we envisage that the next breakthrough anticancer agent is just around the corner.

In this Special Issue, both original research articles and reviews (including scoping reviews) are welcome. Research areas may include, but are not limited to, the following: in silico, artificial intelligence, high-throughput screens, combination therapy, biomarkers, inhibitors, formulation, drug conjugates, tool compounds, drug discovery, and clinical trials.

Dr. David J. Leaver
Dr. Li Li
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 250 words) can be sent to the Editorial Office for assessment.

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • anticancer agents
  • mechanism of action
  • epigenetics
  • PROTAC
  • antibody–drug conjugates
  • enzymes

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Published Papers (2 papers)

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Research

15 pages, 2970 KB  
Article
Synthesis and Evaluation of AS1411-Lenalidomide-Targeted Degradation Chimera in Antitumor Therapy
by Xueling Ma, Shuangshuang Liu, Xiao Dong, Xiuhua Li, Feiyan Wang, Jiawei Zhang, Zhenfang Xu, Weiguo Shi, Aiping Zheng, Aiping Zhang, Xuesong Feng and Liang Xu
Pharmaceuticals 2025, 18(12), 1867; https://doi.org/10.3390/ph18121867 - 7 Dec 2025
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Abstract
Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on [...] Read more.
Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on the principles of PROTAC technology and chemical modification techniques, in this study, a series of AS1411-lenalidomide chimeras featuring different linker structures were designed and synthesized for the specific purpose of targeted degradation of NCL. Four AS1411-PROTACs (C1–C4) were successfully constructed via a click chemistry strategy, and their structures were validated. Results: In vitro experimental results showed that C4 exhibited the most optimal activity, significantly downregulating NCL expression and inhibiting the proliferation of breast cancer cells (MCF-7). Notably, the activity of C4 remained unaltered regardless of the annealing process. Mechanistic studies demonstrated that C4 induced NCL degradation through the ubiquitin–proteasome pathway while also promoting apoptosis and cell cycle arrest. In a nude mouse tumor model, C4 displayed potent antitumor efficacy, with no discernible signs of obvious systemic toxicity. Conclusions: This study provides compelling evidence demonstrating that C4 is a highly promising anticancer compound. It also provides important evidence for the development of novel nucleic acid aptamer–PROTAC conjugate drugs for more clinical applications. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents)
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43 pages, 6125 KB  
Article
Design, Synthesis, and Biological Evaluation of 5′,7-Disubstituted 7-Deaza-adenosine Analogues as Irreversible Pan-FGFR Inhibitors
by Jung Hoon Park, Phuong Thao Tran, Hye Lin Ko, Seonghee Mun, Sung Chul Jang, Dong Hyun Moon, Jaeho Han, Jieun Kim, Gibae Kim, Hongseok Choi, Seung Woo Kim, Minjae Kim, Sang Kook Lee, Byung Woo Han, Keon Wook Kang and Lak Shin Jeong
Pharmaceuticals 2025, 18(11), 1745; https://doi.org/10.3390/ph18111745 - 17 Nov 2025
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Abstract
Background/Objectives: Fibroblast growth factor receptors (FGFRs) are frequently dysregulated in diverse cancers and represent important therapeutic targets. Here, we report the design and synthesis of a novel nucleoside-based scaffold which enables irreversible pan-FGFR inhibition as a potential anticancer strategy. Methods: A [...] Read more.
Background/Objectives: Fibroblast growth factor receptors (FGFRs) are frequently dysregulated in diverse cancers and represent important therapeutic targets. Here, we report the design and synthesis of a novel nucleoside-based scaffold which enables irreversible pan-FGFR inhibition as a potential anticancer strategy. Methods: A series of nucleoside analogues was synthesized and assessed through structure–activity relationship studies. Structural analyses, including X-ray co-crystallography and molecular dynamics simulations, were performed to define key determinants of potency and selectivity. Biochemical assays against FGFR1–4 proteins, cellular antiproliferative assays in HCT116 (FGFR1 amplification) and RT4 (FGFR3-TACC3) models, metabolic stability evaluations and covalent bonding confirmation were conducted to characterize representative compounds. Results: SAR studies revealed that fused aromatic substituents and 4′-thio ribose enhanced FGFR potency, whereas enantiomeric inversion of ribose reduced activity. X-ray co-crystallography further demonstrated that two hydroxyl groups form a key water-mediated hydrogen bond network, uniquely stabilizing the ligand and enhancing potency of inhibitors compared to reference compounds. The 7-methoxy-5-methylbenzo[b]thiophene scaffold and ribose moiety emerged as critical features. Compounds 13f, 19e, and 22f demonstrated potent inhibition of FGFR1-4 and dose-dependent suppression of FGFR1-mediated signaling, with strong antiproliferative activity in both FGFR-driven and wild-type cancer models. Compound 22f showed efficient irreversible covalent engagement of FGFRs, confirmed at the protein and cellular levels, and exhibited improved metabolic stability. Conclusions: Nucleoside analogues represent a privileged scaffold for covalent pan-FGFR inhibition. The findings highlight their potential as promising therapeutic candidates for targeting FGFR-driven malignancies. Future efforts will focus on further improving stability and optimizing physicochemical properties to advance these compounds toward translational development. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors and Protein Degraders as Anticancer Agents)
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