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Protein Kinase Inhibitors for Targeted Anticancer Therapies

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (10 January 2022) | Viewed by 32830

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Dr. Katarzyna Malarz

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A. Chełkowski Institute of Physics and Silesian Center for Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pułku Piechoty 1, 41-500 Chorzów, Poland
Interests: anticancer activity; kinase inhibition; signalling cancer pathways; metal chelators; thiosemicarbazones; oxidative stress
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Dear Colleagues,

Protein kinase inhibitors are one of the most promising groups of drugs for targeted therapies. According to the latest data, 62 small molecule protein kinase inhibitors have been approved by the Federal Drug Administration (FDA) (37 in the last 5 years), while at least 150 are being investigated in clinical trials. This is primarily due to a better understanding of the complex signaling network formed by kinases and their mutual relationship in the signal transduction cascades. The kinase activity controls many signaling pathways responsible for major processes associated with cell growth, proliferation, differentiation, or metabolism. However, despite the growing number of inhibitors, there remain many limitations in this field. The development of resistance based on intrinsic and extrinsic pathways, genomic alterations of the primary target, as well as a short response to targeted therapies due to the activation of compensatory signaling pathways are among the main issues.

The aim of this Special Issue is to highlight original research papers and review articles that provide new insights into the discovery of novel protein kinase inhibitors as well as their application in targeted cancer therapies. Contributions to this Special Issue may focus on exploring new therapeutic targets or identifying novel small molecules, relevant mechanisms, or effective combination therapies.

Dr. Katarzyna Malarz
Guest Editor

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Keywords

drug discovery
small molecules
anticancer activity
targeted cancer therapy
tyrosine kinase inhibitors
serine/threonine kinase inhibitors
allosteric inhibitors
signaling pathways
combination therapy
drug resistance

Related Special Issue

Protein Kinase Inhibitors for Targeted Anticancer Therapies, 2nd Edition in Pharmaceutics (1 article)

Published Papers (10 papers)

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Research

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16 pages, 3865 KiB

Open AccessArticle

The PIK3CA H1047R Mutation Confers Resistance to BRAF and MEK Inhibitors in A375 Melanoma Cells through the Cross-Activation of MAPK and PI3K–Akt Pathways

by Saverio Candido, Rossella Salemi, Sara Piccinin, Luca Falzone and Massimo Libra

Pharmaceutics 2022, 14(3), 590; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030590 - 08 Mar 2022

Cited by 11 | Viewed by 2539

Abstract

The targeting of the Mitogen-Activated Protein Kinase (MAPK) signalling pathway in melanoma improves the prognosis of patients harbouring the V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) mutation. However, a fraction of these patients may experience tumour progression due to resistance to targeted therapy. Mutations affecting the Phosphoinositol-3-Kinase (PI3K)–Akt pathway may favour the onset of drug resistance, suggesting the existence of a crosstalk between the MAPK and PI3K–Akt pathways. We hypothesized that the inhibition of both pathways may be a therapeutic option in resistant melanoma. However, conflicting data have been generated in this context. In this study, three different A375 cell melanoma models either overexpressing or not expressing the wild-type or mutated form of the PhosphatidylInositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene were used to clarify the therapeutic response of melanoma to BRAF, Mitogen-Activated Protein Kinase Kinase 1 (MEK), and PI3K inhibitors in the presence of the PIK3CA H1047R mutation. Our data strongly support the notion that the crosstalk between the MAPK and PI3K–Akt pathways is one of the main mechanisms associated with melanoma development and progression and that the combination of MAPK and PI3K inhibitors may sensitize melanoma cells to therapy. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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22 pages, 6460 KiB

Open AccessArticle

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure

by Jitendra Shrestha, Seong Woong Kim, Su-Bin Kim, Yoon Sin Oh, Sung Hwan Ki, Taeho Lee, Sang-Bum Kim, Taeuk Park, Dong Jae Baek and Eun-Young Park

Pharmaceutics 2022, 14(1), 157; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010157 - 10 Jan 2022

Cited by 1 | Viewed by 2122

Abstract

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR_1–5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1–20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1–10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11–20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC₅₀ = 6.223 µM, HCT116 IC₅₀ = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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12 pages, 1213 KiB

Open AccessArticle

SGC-CK2-1 Is an Efficient Inducer of Insulin Production and Secretion in Pancreatic β-Cells

by Mandy Pack, Claudia Götz, Selina Wrublewsky and Mathias Montenarh

Pharmaceutics 2022, 14(1), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010019 - 22 Dec 2021

Cited by 4 | Viewed by 2157

Abstract

The pyrazolopyrimidine based compound SGC-CK2-1 is a potent and highly specific CK2 inhibitor and a new tool to study the biological functions of protein kinase CK2 irrespective from off-target effects. We used this compound in comparison with the well-established CK2 inhibitor CX-4945 to analyze the importance of CK2 for insulin production and secretion from pancreatic β-cells. Both inhibitors affected the proliferation and viability of MIN6 cells only marginally and downregulated the endogenous CK2 activity to a similar level. Furthermore, both inhibitors increased the message for insulin and boosted the secretion of insulin from storage vesicles. Thus, regarding the high specificity of SGC-CK2-1, we can clearly attribute the observed effects to biological functions of protein kinase CK2. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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18 pages, 2284 KiB

Open AccessArticle

Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations

by Alaa Shafie, Shama Khan, Zehra, Taj Mohammad, Farah Anjum, Gulam Mustafa Hasan, Dharmendra Kumar Yadav and Md. Imtaiyaz Hassan

Pharmaceutics 2021, 13(12), 2157; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122157 - 15 Dec 2021

Cited by 25 | Viewed by 2961

Abstract

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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Review

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28 pages, 1737 KiB

Open AccessReview

Targeting Protein Kinases and Epigenetic Control as Combinatorial Therapy Options for Advanced Prostate Cancer Treatment

by Soghra Bagheri, Mahdie Rahban, Fatemeh Bostanian, Fatemeh Esmaeilzadeh, Arash Bagherabadi, Samaneh Zolghadri and Agata Stanek

Pharmaceutics 2022, 14(3), 515; https://doi.org/10.3390/pharmaceutics14030515 - 25 Feb 2022

Cited by 9 | Viewed by 3561

Abstract

Prostate cancer (PC), the fifth leading cause of cancer-related mortality worldwide, is known as metastatic bone cancer when it spreads to the bone. Although there is still no effective treatment for advanced/metastatic PC, awareness of the molecular events that contribute to PC progression has opened up opportunities and raised hopes for the development of new treatment strategies. Androgen deprivation and androgen-receptor-targeting therapies are two gold standard treatments for metastatic PC. However, acquired resistance to these treatments is a crucial challenge. Due to the role of protein kinases (PKs) in the growth, proliferation, and metastases of prostatic tumors, combinatorial therapy by PK inhibitors may help pave the way for metastatic PC treatment. Additionally, PC is known to have epigenetic involvement. Thus, understanding epigenetic pathways can help adopt another combinatorial treatment strategy. In this study, we reviewed the PKs that promote PC to advanced stages. We also summarized some PK inhibitors that may be used to treat advanced PC and we discussed the importance of epigenetic control in this cancer. We hope the information presented in this article will contribute to finding an effective treatment for the management of advanced PC. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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22 pages, 1179 KiB

Open AccessReview

Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

by Emanuela B. Pucko and Robert P. Ostrowski

Pharmaceutics 2022, 14(2), 331; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020331 - 30 Jan 2022

Cited by 3 | Viewed by 2456

Abstract

In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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27 pages, 2904 KiB

Open AccessReview

Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

by Takahito Kawano, Junichi Inokuchi, Masatoshi Eto, Masaharu Murata and Jeong-Hun Kang

Pharmaceutics 2021, 13(11), 1748; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111748 - 20 Oct 2021

Cited by 35 | Viewed by 4831

Abstract

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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28 pages, 2838 KiB

Open AccessReview

Iterative Upgrading of Small Molecular Tyrosine Kinase Inhibitors for EGFR Mutation in NSCLC: Necessity and Perspective

by Jing Zhu, Qian Yang and Weiguo Xu

Pharmaceutics 2021, 13(9), 1500; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091500 - 18 Sep 2021

Cited by 10 | Viewed by 3645

Abstract

Molecular targeted therapy has been reported to have fewer adverse effects, and offer a more convenient route of administration, compared with conventional chemotherapy. With the development of sequencing technology, and research on the molecular biology of lung cancer, especially whole-genome information on non-small cell lung cancer (NSCLC), various therapeutic targets have been unveiled. Among the NSCLC-driving gene mutations, epidermal growth factor receptor (EGFR) mutations are the most common, and approximately 10% of Caucasian, and more than 50% of Asian, NSCLC patients have been found to have sensitive EGFR mutations. A variety of targeted therapeutic agents for EGFR mutations have been approved for clinical applications, or are undergoing clinical trials around the world. This review focuses on: the indications of approved small molecular kinase inhibitors for EGFR mutation-positive NSCLC; the mechanisms of drug resistance and the corresponding therapeutic strategies; the principles of reasonable and precision molecular structure; and the drug development discoveries of next-generation inhibitors for EGFR. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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10 pages, 769 KiB

Open AccessReview

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

by Frank Aboubakar Nana and Sebahat Ocak

Pharmaceutics 2021, 13(9), 1478; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091478 - 15 Sep 2021

Cited by 9 | Viewed by 4369

Abstract

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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23 pages, 2607 KiB

Open AccessReview

Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

by Annette K. Brenner and Maria W. Gunnes

Pharmaceutics 2021, 13(9), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091427 - 08 Sep 2021

Cited by 11 | Viewed by 2679

Abstract

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment regimens are probably less likely to induce drug resistance, a special focus will be on the combination of ALK inhibitors with drugs that either target downstream signalling pathways or that affect the survival and proliferation of cancer cells in general. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors for Targeted Anticancer Therapies)

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