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New Insights into Kinase Inhibitors
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New Insights into Kinase Inhibitors

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

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 39487

Special Issue Editor

Dr. Roberta Bortolozzi

E-Mail Website1 Website2
Guest Editor
1. Experimental Pharmacology Laboratory, Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
2. Dipartimento Salute della Donna e del Bambino, Università degli Studi di Padova, Padua, Italy
Interests: anticancer compounds; chemotherapy resistance; kinase inhibitors; antimitotic compounds; cancer pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last 30 years kinases has been widely studied as drug target to inhibit proliferation and angiogenesis for cancer therapy. Kinase inhibitors now represent one of the major class of chemotherapeutics, with 52 kinase inhibitors approved as anticancer agents.

538 kinase are active in human body and are responsible for the phosphorylation of up to one-third of proteome controlling migration, survival, proliferation and other processes through phosphorylation cascades. Moreover, aberrant kinase activity has been described to have important role not only in cancer but also in inflammatory, degenerative, immunological, metabolic, cardiovascular diseases.

Although druggability and clinical safety profile make kinases attractive targets, the majority of kinases are still unexplored and the field of kinase inhibitors is still growing.

This special issue will highlight the new insight into the discovery of new kinase inhibitors, from the investigation of new targets to the identification of novel small molecules. Contribution to this issue, both in the form of original article or review, may focus on powerful strategies and technological advances in the synthesis of more efficient and selective compounds, new strategies to overcome kinase inhibitors resistance and improvement on the use of kinase inhibitors in oncology and in other pathologies, considering therapeutic combinations with less toxic and off-target effects.

Dr. Roberta Bortolozzi
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

  • kinase inhibitors
  • kinase inhibitors chemistry
  • therapy resistance
  • combination therapy
  • antitumoral activity

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Published Papers (9 papers)

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Research

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12 pages, 2171 KiB  
Article
Pan-ROCK and ROCK2 Inhibitors Affect Dexamethasone-Treated 2D- and 3D-Cultured Human Trabecular Meshwork (HTM) Cells in Opposite Manners
by Megumi Watanabe, Yosuke Ida, Masato Furuhashi, Yuri Tsugeno, Fumihito Hikage and Hiroshi Ohguro
Molecules 2021, 26(21), 6382; https://doi.org/10.3390/molecules26216382 - 22 Oct 2021
Cited by 9 | Viewed by 2325
Abstract
Effects of a pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025 on dexamethasone (DEX)-treated human trabecular meshwork (HTM) cells as a model of steroid-induced glaucoma were investigated. In the presence of Rip or KD025, DEX-treated HTM cells were subjected to permeability analysis of [...] Read more.
Effects of a pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025 on dexamethasone (DEX)-treated human trabecular meshwork (HTM) cells as a model of steroid-induced glaucoma were investigated. In the presence of Rip or KD025, DEX-treated HTM cells were subjected to permeability analysis of 2D monolayer by transendothelial electrical resistance (TEER) and FITC–dextran permeability, physical properties, size and stiffness analysis (3D), and qPCR of extracellular matrix (ECM), and their modulators. DEX resulted in a significant increase in the permeability, as well as a large and stiff 3D spheroid, and those effects were inhibited by Rip. In contrast, KD025 exerted opposite effects on the physical properties (down-sizing and softening). Furthermore, DEX induced several changes of gene expressions of ECM and their modulators were also modulated differently by Rip and KD025. The present findings indicate that Rip and KD025 induced opposite effects toward 2D and 3D cell cultures of DEX-treated HTM cells. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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18 pages, 4859 KiB  
Article
Sensitization to Drug Treatment in Precursor B-Cell Acute Lymphoblastic Leukemia Is Not Achieved by Stromal NF-κB Inhibition of Cell Adhesion but by Stromal PKC-Dependent Inhibition of ABC Transporters Activity
by Paola Fernanda Ruiz-Aparicio, Gloria Inés Uribe, Adriana Linares-Ballesteros and Jean-Paul Vernot
Molecules 2021, 26(17), 5366; https://doi.org/10.3390/molecules26175366 - 3 Sep 2021
Cited by 6 | Viewed by 2252
Abstract
Cell adhesion to stromal support and the associated intracellular signaling are central to drug resistance, therefore blocking both has been effective in increasing drug sensitization in leukemia. The stromal Ser/Thr protein kinase C (PKC) has been found to be important for conferring protection [...] Read more.
Cell adhesion to stromal support and the associated intracellular signaling are central to drug resistance, therefore blocking both has been effective in increasing drug sensitization in leukemia. The stromal Ser/Thr protein kinase C (PKC) has been found to be important for conferring protection to leukemic cells. We aimed at elucidating the intracellular signals connected to cell adhesion and to stromal PKC. We found that NF-κB and Akt were up-regulated in mesenchymal stem cells (MSC) after binding of B-cell acute lymphoblastic leukemia (B-ALL) cells. Nevertheless, Akt inhibition did not induce B-ALL cell detachment. In spite of a clear activation of the NF-κB signaling pathway after B-ALL cell binding (up-regulation NF-κB1/2, and down-regulation of the IKBε and IKBα inhibitors) and an important reduction in cell adhesion after NF-κB inhibition, sensitization to the drug treatment was not observed. This was opposite to the PKC inhibitors Enzastaurin and HKPS, a novel chimeric peptide inhibitor, that were able to increase sensitization to dexamethasone, methotrexate, and vincristine. PLCγ1, Erk1/2, and CREB appear to be related to PKC signaling and PKC effect on drug sensitization since they were contra-regulated by HKPS when compared to dexamethasone-treated cells. Additionally, PKC inhibition by HKPS, but not by Enzastaurin, in MSC reduced the activity of three ABC transporters in leukemic cells treated with dexamethasone, a new indirect mechanism to increase sensitization to drug treatment in B-ALL cells. Our results show the validity of targeting the functional characteristic acquired and modulated during cell-to-cell interactions occurring in the leukemic niche. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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12 pages, 18350 KiB  
Article
Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening
by Ahmed Elkamhawy, Usama M. Ammar, Sora Paik, Magda H. Abdellattif, Mohamed H. Elsherbeny, Kyeong Lee and Eun Joo Roh
Molecules 2021, 26(17), 5324; https://doi.org/10.3390/molecules26175324 - 1 Sep 2021
Cited by 10 | Viewed by 3024
Abstract
Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over [...] Read more.
Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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8 pages, 211 KiB  
Article
Machine Learning Approaches to Predict Hepatotoxicity Risk in Patients Receiving Nilotinib
by Jung-Sun Kim, Ji-Min Han, Yoon-Sook Cho, Kyung-Hee Choi and Hye-Sun Gwak
Molecules 2021, 26(11), 3300; https://doi.org/10.3390/molecules26113300 - 31 May 2021
Cited by 6 | Viewed by 2617
Abstract
Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using [...] Read more.
Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61–0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
28 pages, 7600 KiB  
Article
Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer
by Ashraf N. Abdalla, Waleed H. Malki, Amal Qattan, Imran Shahid, Mohammad Akbar Hossain and Muhammad Ahmed
Molecules 2021, 26(2), 334; https://doi.org/10.3390/molecules26020334 - 11 Jan 2021
Cited by 23 | Viewed by 4883
Abstract
Colorectal cancer (CRC) remains one of the main causes of death worldwide and in Saudi Arabia. The toxicity and the development of resistance against 5 fluorouracil 5FU pose increasing therapeutic difficulties, which necessitates the development of personalized drugs and drug combinations. Objectives: First, [...] Read more.
Colorectal cancer (CRC) remains one of the main causes of death worldwide and in Saudi Arabia. The toxicity and the development of resistance against 5 fluorouracil 5FU pose increasing therapeutic difficulties, which necessitates the development of personalized drugs and drug combinations. Objectives: First, to determine the most important kinases and kinase pathways, and the amount of ABC transporters and KRAS in samples taken from Saudi CRC patients. Second, to investigate the chemosensitizing effect of LY294002 and HAA2020 and their combinations with 5FU on HT29, HT29-5FU, HCT116, and HCT116-5FU CRC cells, their effect on the three ABC transporters, cell cycle, and apoptosis, in light of the important kinase pathways resulting from the first part of this study. Methods: The PamChip® peptide micro-array profiling was used to determine the level of kinase and targets in the Saudi CRC samples. Next, RT-PCR, MTT cytotoxicity, Western blotting, perturbation of cell cycle, annexin V, and immunofluorescence assays were used to investigate the effect on CRC, MRC5, and HUVEC cells. Results: The kinase activity profiling highlighted the importance of the PI3K/AKT, MAPK, and the growth factors pathways in the Saudi CRC samples. PIK3CA was the most overexpressed, and it was associated with increased level of mutated KRAS and the three ABC transporters, especially ABCC1 in the Saudi samples. Next, combining HAA2020 with 5FU exhibited the best synergistic and resistance-reversal effect in the four CRC cells, and the highest selectivity indices compared to MRC5 and HUVEC normal cells. Additionally, HAA2020 with 5FU exerted significant inhibition of ABCC1 in the four CRC cells, and inhibition of PIK3CA/AKT/MAPK7/ERK in HT29 and HT29-5FU cells. The combination also inhibited EGFR, increased the preG1/S cell cycle phases, apoptosis, and caspase 8 in HT29 cells, while it increased the G1 phase, p21/p27, and apoptosis in HT29-5FU cells. Conclusion: We have combined the PamChip kinase profiling of Saudi CRC samples with in vitro drug combination studies in four CRC cells, highlighting the importance of targeting PIK3CA and ABCC1 for Saudi CRC patients, especially given that the overexpression of PIK3CA mutations was previously linked with the lack of activity for the anti-EGFRs as first line treatment for CRC patients. The combination of HAA2020 and 5FU has selectively sensitized the four CRC cells to 5FU and could be further studied. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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22 pages, 6546 KiB  
Article
Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents
by Dima A. Sabbah, Shaima’ E. Hasan, Reema Abu Khalaf, Sanaa K. Bardaweel, Rima Hajjo, Khalid M. Alqaisi, Kamal A. Sweidan and Aya M. Al-Zuheiri
Molecules 2020, 25(22), 5348; https://doi.org/10.3390/molecules25225348 - 16 Nov 2020
Cited by 11 | Viewed by 2498
Abstract
The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives [...] Read more.
The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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Review

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26 pages, 3700 KiB  
Review
Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy
by Ozge Tatli and Gizem Dinler Doganay
Molecules 2021, 26(24), 7561; https://doi.org/10.3390/molecules26247561 - 14 Dec 2021
Cited by 4 | Viewed by 5184
Abstract
Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered [...] Read more.
Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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21 pages, 23145 KiB  
Review
Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors
by Francis Giraud, Elisabeth Pereira, Fabrice Anizon and Pascale Moreau
Molecules 2021, 26(9), 2696; https://doi.org/10.3390/molecules26092696 - 4 May 2021
Cited by 17 | Viewed by 4654
Abstract
The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, [...] Read more.
The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR–Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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30 pages, 1300 KiB  
Review
Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer
by Naheed Arfin Borah and Mamatha M. Reddy
Molecules 2021, 26(7), 1981; https://doi.org/10.3390/molecules26071981 - 1 Apr 2021
Cited by 89 | Viewed by 10547
Abstract
Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in [...] Read more.
Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors)
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