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New Insights into Kinase Inhibitors II

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

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 4144

Special Issue Editor


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
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Special Issue Information

Dear Colleagues,

This issue is a continuation of the previous successful Special Issue “New Insights into Kinase Inhibitors”.

In the last 30 years, kinases have been widely studied as drug targets to inhibit proliferation and angiogenesis in cancer therapy. Kinase inhibitors now represent one of the major classes of chemotherapeutics, with 52 kinase inhibitors having been approved as anticancer agents.

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

Although their 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 new insights into the discovery of new kinase inhibitors, from the investigation of new targets to the identification of novel small molecules. Contributions to this issue, both in the form of original articles or reviews, 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 improvements regarding the use of kinase inhibitors in oncology and other pathologies, in which therapeutic combinations with less toxic and off-target effects are considered.

Dr. Roberta Bortolozzi
Guest Editor

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Keywords

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

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Published Papers (3 papers)

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Research

18 pages, 1939 KiB  
Article
Adaptation of the Mitsunobu Reaction for Facile Synthesis of Dorsomorphin-Based Library
by Daria Novikova, Svetlana Vorona, Anastasiya Zenina, Tatyana Grigoreva and Vyacheslav Tribulovich
Molecules 2025, 30(11), 2258; https://doi.org/10.3390/molecules30112258 - 22 May 2025
Viewed by 110
Abstract
Pyrazolo[1,5-a]pyrimidine is a nitrogen-containing fused heterocycle that imitates the nitrogenous base adenine with varying degrees of reliability. This fact determines its frequent use in drug design, including the development of ATP-competitive kinase inhibitors. These include dorsomorphin which shows compromised kinase selectivity but is [...] Read more.
Pyrazolo[1,5-a]pyrimidine is a nitrogen-containing fused heterocycle that imitates the nitrogenous base adenine with varying degrees of reliability. This fact determines its frequent use in drug design, including the development of ATP-competitive kinase inhibitors. These include dorsomorphin which shows compromised kinase selectivity but is still widely used as an AMPK inhibitor. ATP-binding pockets of many proteins have a fairly conservative spatial structure and there is a high probability of obtaining a compound with low target selectivity during drug development. In the case of a common scaffold, the careful selection of side substituents that determine the activity and selectivity of the final compound plays an important role. In this work, a convergent strategy for the synthesis of dorsomorphin and its close analogs was developed and implemented. The resulting small series of compounds is distinguished by the maximum possible diversification and allows for an assessment of the biological activity towards AMPK. An original route to obtain variants of the phenoxy-alkylamine moiety of dorsomorphin via the Mitsunobu reaction will be useful for generating targeted-focused libraries of ATP-competitive kinase inhibitors and highly active receptor ligands. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors II)
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16 pages, 2775 KiB  
Article
A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network
by Lidia Boghean, Sarbjit Singh, Kiran K. Mangalaparthi, Smitha Kizhake, Lelisse Umeta, Donn Wishka, Paul Grothaus, Akhilesh Pandey and Amarnath Natarajan
Molecules 2025, 30(9), 2001; https://doi.org/10.3390/molecules30092001 - 30 Apr 2025
Viewed by 249
Abstract
The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a [...] Read more.
The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors II)
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15 pages, 8550 KiB  
Article
In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones
by Kamonpan Sanachai, Panupong Mahalapbutr, Lueacha Tabtimmai, Supaphorn Seetaha, Nantawat Kaekratoke, Supakarn Chamni, Syed Sikander Azam, Kiattawee Choowongkomon and Thanyada Rungrotmongkol
Molecules 2023, 28(2), 597; https://doi.org/10.3390/molecules28020597 - 6 Jan 2023
Cited by 4 | Viewed by 2934
Abstract
Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, [...] Read more.
Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2′-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 μM) and HEL (IC50 = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs. Full article
(This article belongs to the Special Issue New Insights into Kinase Inhibitors II)
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