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Small Molecule Inhibitors as Anticancer Drugs: Advances and Challenges

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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 June 2023) | Viewed by 13202

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Special Issue Editors

Dr. Santo Previti

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Guest Editor

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
Interests: medicinal chemistry; drug design; peptide chemistry; peptidomimetics; small molecules; structure–activity relationships studies; cysteine protease inhibitors; neurotensin analogues
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Maria Zappalà

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Guest Editor

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
Interests: medicinal chemistry; drug design; peptidomimetics, small molecules; structure–activity relationships studies; cysteine protease inhibitors; proteasome inhibitors

Special Issue Information

Dear Colleagues，

Chemotherapy was for a long time the first choice for cancer treatment, along with surgery and radiotherapy. Chemotherapeutic drugs kill tumor cells, but their inability to distinguish cancer and non-cancerous cells results in relevant adverse effects. At the beginning of the new millennium, great efforts made by scientists led to the approval of Imatinib, which could be considered the first small molecule with targeted anticancer activity. Compared to the outdated anticancer therapies, small molecule targeted drugs can selectively target tumor cells with limited toxicity. Over the last 20 years, about 90 anti-cancer small molecules have been approved around the world, and an increasing number of candidates are in clinical trials. Among the possible strategies, the inhibition of protein kinases, both receptor and non-receptor kinases, proteasome, poly (ADP-ribose) polymerases (PARPs), and B-cell lymphoma 2 (BCL-2) proteins, as well as the modulation of epigenetic and hedgehog pathways, represent valid and precious approaches for the development of targeted drugs. Despite the promising advances in cancer therapy, the small-molecule targeted cancer-fighting drugs still face challenges that limit the successful treatment. Drug resistance and low efficacy are the main limiting factors affecting most cancer patients. Several cellular and molecular paradigms influence the drug resistance onset, meanwhile, the efficacy of targeted anti-cancer drugs is restricted in a limited number of patients, mainly due to mutations and gene rearrangements. However, different strategies to overcome these issues were carried-out: the discovery of new anti-cancer targets, the use of small molecules in combination therapies, the antibody-drug conjugates, and the PROTAC technology could significantly improve the cancer treatment.

This Special Issue aims to collect reviews and research articles concerning small molecule-drugs in targeted cancer therapy. The rational analysis of the obtained findings so far and new investigation studies could provide precious information for the research and development of small molecules with targeted anticancer activity.

Dr. Santo Previti
Prof. Dr. Maria Zappalà
Guest Editors

Manuscript Submission Information

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Keywords

anticancer
small molecules
targeted anticancer therapy
drug resistance
protein kinases
epigenetic
proteasome
PROTAC

Published Papers (4 papers)

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Research

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21 pages, 4179 KiB

Open AccessArticle

Identification of Dihydrolipoamide Dehydrogenase as Potential Target of Vemurafenib-Resistant Melanoma Cells

by Claudio Tabolacci, Deborah Giordano, Stefania Rossi, Martina Cordella, Daniela D’Arcangelo, Federica Moschella, Stefania D’Atri, Mauro Biffoni, Angelo Facchiano and Francesco Facchiano

Molecules 2022, 27(22), 7800; https://doi.org/10.3390/molecules27227800 - 12 Nov 2022

Cited by 3 | Viewed by 2007

Abstract

Background: Despite recent improvements in therapy, the five-year survival rate for patients with advanced melanoma is poor, mainly due to the development of drug resistance. The aim of the present study was to investigate the mechanisms underlying this phenomenon, applying proteomics and structural approaches to models of melanoma cells. Methods: Sublines from two human (A375 and SK-MEL-28) cells with acquired vemurafenib resistance were established, and their proteomic profiles when exposed to denaturation were identified through LC-MS/MS analysis. The pathways derived from bioinformatics analyses were validated by in silico and functional studies. Results: The proteomic profiles of resistant melanoma cells were compared to parental counterparts by taking into account protein folding/unfolding behaviors. Several proteins were found to be involved, with dihydrolipoamide dehydrogenase (DLD) being the only one similarly affected by denaturation in all resistant cell sublines compared to parental ones. DLD expression was observed to be increased in resistant cells by Western blot analysis. Protein modeling analyses of DLD’s catalytic site coupled to in vitro assays with CPI-613, a specific DLD inhibitor, highlighted the role of DLD enzymatic functions in the molecular mechanisms of BRAFi resistance. Conclusions: Our proteomic and structural investigations on resistant sublines indicate that DLD may represent a novel and potent target for overcoming vemurafenib resistance in melanoma cells. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors as Anticancer Drugs: Advances and Challenges)

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12 pages, 3963 KiB

Open AccessArticle

Structure-Based Discovery and Biological Assays of a Novel PRMT5 Inhibitor for Non-Small Cell Lung Cancer

by Yingqing Chen, Mingyu Zhang, Anxin Wu, Xiaojun Yao and Qianqian Wang

Molecules 2022, 27(21), 7436; https://doi.org/10.3390/molecules27217436 - 01 Nov 2022

Cited by 4 | Viewed by 2051

Abstract

Protein arginine methyltransferase 5 (PRMT5) is a popular anticancer target that regulates histone or nonhistone methylation and is linked to the development and poor prognosis of non-small cell lung cancer. PRMT5 inhibitors have shown great promise in clinical trials as a cancer therapy. However, most inhibitors reported recently act in a SAM-competitive mode and lack structural diversity. In this paper, a novel non-SAM inhibitor, 3039-0164, was discovered by the structure-based virtual screening method. The binding mechanism of 3039-0164 to PRMT5 was revealed via molecular docking and molecular dynamics simulations. 3039-0164 inhibited PRMT5 enzymatic activity, downregulated the expression of PRMT5 downstream target genes (FGFR3 and eIF4E), and blocked the activation of the PI3K/AKT/mTOR and ERK signaling pathways. The discovery of 3039-0164 provides precise and creative hit compounds for the design optimization of PRMT5 lead compounds in non-small cell lung cancer. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors as Anticancer Drugs: Advances and Challenges)

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Review

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38 pages, 4546 KiB

Open AccessReview

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

by Kenneth K. W. To, Enming Xing, Ross C. Larue and Pui-Kai Li

Molecules 2023, 28(7), 3043; https://doi.org/10.3390/molecules28073043 - 29 Mar 2023

Cited by 11 | Viewed by 4977

Abstract

The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors as Anticancer Drugs: Advances and Challenges)

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50 pages, 3289 KiB

Open AccessFeature PaperReview

Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges

by Monica A. Kamal, Yasmine M. Mandour, Mostafa K. Abd El-Aziz, Ulrike Stein and Hend M. El Tayebi

Molecules 2022, 27(17), 5537; https://doi.org/10.3390/molecules27175537 - 28 Aug 2022

Cited by 9 | Viewed by 3294

Abstract

According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors as Anticancer Drugs: Advances and Challenges)

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