Off-target effects of tyrosine kinase inhibitors: Beauty or the Beast?

Zhang, Ranran; Loughran, Thomas P.

doi:10.3109/10428194.2011.560694

Cited by 8 publications

(4 citation statements)

References 17 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lestaurtinib has been reported to be a multi-kinase inhibitor, specifically of the JAK2 signaling pathway[ 24 ]; however, many kinase inhibitors have off target effects[ 26 , 27 ], making their true anti-cancer mechanism unclear. In this study, we have reported the effects of Lestaurtinib in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

et al. 2018

View full text Add to dashboard Cite

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.

show abstract

Section: Discussionmentioning

confidence: 99%

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Many kinase inhibitors are characterized as having off-target effects, making it unclear what their true anti-cancer mechanism is [ 25 , 26 ]. To assess whether specific CDK9 inhibition alone could result in an antiproliferative effect, we knocked down CDK9 (siCDK9) in CAL62 and KMH2 cell lines and compared it to a scrambled control.…”

Section: Resultsmentioning

confidence: 99%

Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models

et al. 2020

View full text Add to dashboard Cite

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.

show abstract

“…Protein kinases share homologous primary sequence, conserved folding scaffold, and analogous biological function, and many kinase inhibitors therefore exhibit considerable promiscuity and broad specificity that may interact with a wide array of protein kinases and kinase mutants . It is hypothesized that certain protein kinases involved in the pathogenesis of TN can be targeted unexpectedly by multiple kinase inhibitors to elicit therapeutic potency on the disease.…”

Section: Introductionmentioning

confidence: 99%

“…8 Protein kinases share homologous primary sequence, conserved folding scaffold, and analogous biological function, and many kinase inhibitors therefore exhibit considerable promiscuity and broad specificity that may interact with a wide array of protein kinases and kinase mutants. 9,10 It is hypothesized that certain protein kinases involved in the pathogenesis of TN can be targeted unexpectedly by multiple kinase inhibitors to elicit therapeutic potency on the disease. Although there probably is an association between the potency and unexpected kinase-inhibitor interactions (UKIIs) 11 in the kinase-regulated signaling cascade of TN, the underlying molecular mechanism and biological implication still remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Statistical analysis and heuristic identification of unexpected interactions from the neurokinase‐inhibitor interactome in trigeminal neuralgia pharmacological intervention

Liu

Chen

Liu

et al. 2019

Journal of Chemometrics

View full text Add to dashboard Cite

The cell signaling pathways of human trigeminal neuralgia (TN) are orchestrated by a variety of protein kinase‐elicited phosphorylation events. However, a majority of TN‐related neurokinases have not yet been revealed and still remain largely unexplored. Here, a systematic kinase‐inhibitor interactome for 601 small‐molecule inhibitors across 51 human neurokinases is created via a high‐throughput molecular docking procedure; the inhibitors are reversible, ATP competitive, and commercially available, while the kinases are enriched by gene ontology (GO) to be semantically relevant with TN and have cocrystallized structures with their cognate ligands. Heuristic clustering and statistical analysis identify 35 hit inhibitors from the interactome profile, which are potential to target TN‐related kinases. The intermolecular interactions of four promising inhibitors with the array of 51 TN‐related kinases are investigated in detail at molecular level using dynamics simulation and energetics analysis. Consequently, a total of nine protein kinases are inferred as high‐affinity cotargets of these potent inhibitors, in which fours have already been established as sophisticated targets for TN therapy, while others are still unclear about their therapeutic implications underlying the disease. Some candidates are selected as representatives to perform kinase assay. It is found that some putative kinase targets can be inhibited effectively by noncognate inhibitors; the activity values are comparable with or even better than known cognate inhibitors. Structural examination of a potent kinase‐inhibitor complex identifies a number of noncovalent interactions such as hydrogen bonds, cation‐π stacking, and hydrophobic contacts at the tightly packed complex interface, conferring both stability and specificity to the complex recognition and interaction.

show abstract

Off-target effects of tyrosine kinase inhibitors: Beauty or the Beast?

Cited by 8 publications

References 17 publications

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models

Statistical analysis and heuristic identification of unexpected interactions from the neurokinase‐inhibitor interactome in trigeminal neuralgia pharmacological intervention

Contact Info

Product

Resources

About