Protein Kinase Inhibitors for Targeted Anticancer Therapies, 2nd Edition

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

Deadline for manuscript submissions: 30 June 2024 | Viewed by 1211

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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 currently being investigated in clinical trials. This is primarily due to a better understanding of the complex signaling network formed by kinases and their mutual relationships in signal transduction cascades. Kinase activity controls many of the signaling pathways responsible for major processes associated with cell growth, proliferation, differentiation, and metabolism. However, despite the growing number of inhibitors, many limitations remain in this field. The development of resistance based on intrinsic and extrinsic pathways, genomic alterations of the primary target, and 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

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Published Papers (1 paper)

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Research

16 pages, 2948 KiB  
Article
Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax
by Thao M. Nguyen, Paul Joyce, David M. Ross, Kristen Bremmell, Manasi Jambhrunkar, Sook S. Wong and Clive A. Prestidge
Pharmaceutics 2024, 16(2), 209; https://doi.org/10.3390/pharmaceutics16020209 - 31 Jan 2024
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Abstract
MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and [...] Read more.
MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML’s heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1–0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou–Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5–250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML. Full article
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