The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

Malarz, Katarzyna; Mularski, Jacek; Pacholczyk, Marcin; Musioł, Robert

doi:10.3390/cancers12030536

Cited by 8 publications

(5 citation statements)

References 67 publications

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“…The change in this transcript’s level was related to the influence of the sulfonic styrylquinazolines on the overall cellular metabolism and the inhibition of cell proliferation and growth. This is supported by several reports, which revealed the potency of the sulfonamide analogs as mutant IDH1 or dual IDH1/ABL inhibitors [ 32 , 59 , 60 ]. It is worth noting that a decreased IDH1 expression may prevent the overproduction of onco-metabolites, which can usually positively regulate the HIF pathways that are involved in angiogenesis, invasion and metastasis [ 61 ].…”

Section: Resultssupporting

confidence: 72%

“…Interestingly, all of the compounds interacted with the BTK and Lck kinases in an inhibition range from 9% to 43% (see in Table 2 ). It is worth noting that oncogenic BTK kinase is highly expressed in leukemia cells, which may explain the susceptibility of these cells to the tested compounds to some degree [ 32 , 33 ]. Moreover, several reports have shown that BTK kinase is an important element of the cascade of the signal transduction from BCR-ABL through Lyn and Syk, which leads to calcium release, cell proliferation and the activation of the NF-κB pathway [ 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

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Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Malarz

Mularski

Kuczak

et al. 2021

Cancers

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Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

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Section: Resultssupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Malarz

Mularski

Kuczak

et al. 2021

Cancers

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“…We chose these two cell lines because of their characteristics, including high levels of BTK expression, as reported previously. 32,33 The tested nanomaterial resulted in good antiproliferative activity against RAJI cells. The calculated IC 50 parameter was 350 µM (Figure 4A).…”

Section: Immunoblottingmentioning

confidence: 99%

Identification and Biological Evaluation of a Water-Soluble Fullerene Nanomaterial as BTK Kinase Inhibitor

Malarz¹,

Korzuch²,

Marforio³

et al. 2023

IJN

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Introduction Thanks to recent advances in synthetic methodology, water-soluble fullerene nanomaterials that interfere with biomolecules, especially DNA/RNA and selected proteins, have been found with tremendous potential for applications in nanomedicine. Herein, we describe the synthesis and evaluation of a water-soluble glycine-derived [60]fullerene hexakisadduct (HDGF) with T h symmetry, which is a first-in-class BTK protein inhibitor. Methods We synthesized and characterized glycine derived [60]fullerene using NMR, ESI-MS, and ATR-FT-IR. DLS and zeta potential were measured and high-resolution transmission electron microscopy (HRTEM) observations were performed. The chemical composition of the water-soluble fullerene nanomaterial was examined by X-ray photoelectron spectrometry. To observe aggregate formation, the cryo-TEM analysis was carried out. The docking studies and molecular dynamic simulations were performed to determine interactions between HDGF and BTK. The in vitro cytotoxicity was evaluated on RAJI and K562 blood cancer cell lines. Subsequently, we examined the induction of cell death by autophagy and apoptosis by determining the expression levels of crucial genes and caspases. We investigated the direct association of HDGF on inhibition of the BTK signalling pathway by examining changes in the calcium levels in RAJI cells after treatment. The inhibitory potential of HDGF against non-receptor tyrosine kinases was evaluated. Finally, we assessed the effects of HDGF and ibrutinib on the expression of the BTK protein and downstream signal transduction in RAJI cells following anti-IgM stimulation. Results Computational studies revealed that the inhibitory activity of the obtained [60]fullerene derivative is multifaceted: it hampers the BTK active site, interacting directly with the catalytic residues, rendering it inaccessible to phosphorylation, and binds to residues that form the ATP binding pocket. The anticancer activity of produced carbon nanomaterial revealed that it inhibited the BTK protein and its downstream pathways, including PLC and Akt proteins, at the cellular level. The mechanistic studies suggested the formation of autophagosomes (increased gene expression of LC3 and p62 ) and two caspases (caspase-3 and −9) were responsible for the activation and progression of apoptosis. Conclusion These data illustrate the potential of fullerene-based BTK protein inhibitors as nanotherapeutics for blood cancer and provide helpful information to support the future development of fullerene nanomaterials as a novel class of enzyme inhibitors.

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“…Chelating metal ions can be a promising approach to designing novel and effective anticancer drugs. In our recent work, several scaffolds were evaluated for their potency as biologically active chelating and ionophoric agents, including quinolones [ 59 , 60 , 61 ], quinazolines [ 62 , 63 , 64 ], and thiosemicarbazones [ 65 , 66 , 67 , 68 ]. More recently, we have investigated terpyridines (Tpy) that possess strong chelating activity and potential for development [ 69 ].…”

Section: Should We Have Complexes With Terpyridines?mentioning

confidence: 99%

Chemistry towards Biology—Instruct: Snapshot

Hricovíni

Owens

Bąk

et al. 2022

IJMS

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The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.

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The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

Cited by 8 publications

References 67 publications

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Identification and Biological Evaluation of a Water-Soluble Fullerene Nanomaterial as BTK Kinase Inhibitor

Chemistry towards Biology—Instruct: Snapshot

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