A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma

Fawwaz, Muammar; Mishiro, Kenji; Nishii, Ryuichi; Makino, Akihiro; Kiyono, Yasushi; Shiba, Kazuhiro; Kinuya, Seigo; Ogawa, Kenji

doi:10.3390/ph14030256

Cited by 8 publications

(8 citation statements)

References 29 publications

(52 reference statements)

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“…As a result, [ 77 Br]Br – is distributed to some organs, and its radioactivity is retained for a long time. 77 Br-labeled CO-1686, [ 77 Br]BrCO1686, showed delayed blood clearance derived from its debromination . Meanwhile, in in vitro stability experiments in a buffered solution, approximately 15% of [ 125 I] 9 and [ 77 Br] 15 was decomposed to free iodine and free bromine after 24 h of incubation.…”

Section: Resultsmentioning

confidence: 99%

“…77 Br-labeled CO-1686, [ 77 Br]BrCO1686, showed delayed blood clearance derived from its debromination. 23 Meanwhile, in in vitro stability experiments in a buffered solution, approximately 15% of [ 125 I] 9 and [ 77 Br]15 was decomposed to free iodine and free bromine after 24 h of incubation. However, the in vivo deiodination and debromination of the tracers barely occurred as mentioned above.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…However, the potential of these radiotracers as imaging probes targeting EGFR-TK with L858R/T790M double mutations was not assessed . Recently, we reported radiolabeled probes targeting EGFR-TK with L858R/T790M double mutations, [ 125 I]ICO1686 and [ 77 Br]BrCO1686 (Figure ), using rociletinib (CO-1686) as a lead compound. , [ 125 I]ICO1686 and [ 77 Br]BrCO1686 could detect the EGFR with L858R/T790M double mutations in vitro ; however, in experiments using tumor-bearing mice, these tracers did not sufficiently accumulate in tumors with L858R/T790M double mutations.…”

Section: Introductionmentioning

confidence: 99%

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Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

et al. 2022

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Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

et al. 2022

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“…The H358, H2170, H3255 and H1975 cell lines were cultured with 5% CO 2 at 37 °C following the protocol of the American Type Culture Collection (ATCC). The H2170 and H358 cell lines have EGFR wild-type status, while H1975 has two EGFR tyrosine kinase domain mutations—L858R and T790M [ 26 , 27 ]. H3255 has a single EGFR tyrosine kinase domain mutation-L858R [ 27 , 28 ].…”

Section: Methodsmentioning

confidence: 99%

PRMT-1 and p120-Catenin as EMT Mediators in Osimertinib Resistance in NSCLC

Racherla

Dovalovsky

Patel

et al. 2023

Cancers

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Osimertinib, an irreversible tyrosine kinase inhibitor, is a first-line therapy in EGFR-mutant NSCLC patients. Prolonged treatment with Osimertinib leads to resistance due to an acquired C797S mutation in the EGFR domain and other mechanisms, such as epithelial-mesenchymal transition (EMT). In this study, we investigated the role of PRMT-1 and p120-catenin in mediating Osimertinib resistance (OR) through EMT. These studies found upregulation of gene and protein expression of PRMT-1, p120-catenin and Kaiso factor. Knockdown of p120-catenin using siRNA increased OR efficacy by 45% as compared to cells treated with mock siRNA and OR. After 24 h of transfection, the percentage wound closure in cells transfected with p120-catenin siRNA was 26.2%. However, in mock siRNA-treated cells the wound closure was 7.4%, showing its involvement in EMT. We also found high levels of p120-catenin expressed in 30% of smokers as compared to 5.5% and 0% of non-smokers and quit-smokers (respectively) suggesting that smoking may influence p120-catenin expression in NSCLC patients. These results suggest that biomarkers such as PRMT-1 may mediate EMT by methylating Twist-1 and increasing p120-catenin expression, which causes transcriptional activation of genes associated with Kaiso factor to promote EMT in Osimertinib-resistant cells.

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“…However, the radiotracers employed in the imaging of double mutations of EGFR T790M/L858R, such as [ 11 C]osimertinib, [ 11 C]rociletinib, [ 125 I]ICO1686, [ 77 Br]BrCO1686, [ 125 I]I-osimertinib, and [ 77 Br]Br-osimertinib have some limitations, such as low accumulation in the targeted tumor, which results in insufficient tumor-to-blood ratios or tumor-to-nontarget tissue ratios. 11 - 13 , 15 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and initial in vitro evaluation of olmutinib derivatives as prospective imaging probe for non-small cell lung cancer

Fawwaz,

Mishiro,

Arwansyah

et al. 2023

Bioimpacts

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Introduction: Imaging a non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitors (TKIs) has attracted attention due to their unique interaction with the target epidermal growth factor receptor (EGFR). Olmutinib (OTB) is one of the third-generation EGFR TKIs, which selectively inhibit EGFR L858R/T790M mutation. In this study, we aim to estimate the interaction of the iodinated OTB (I-OTB)-receptor complex by molecular docking. Furthermore, we will synthesize the I-OTB and evaluate its activity toward EGFR L858R/T790M by in vitro cytotoxicity assay. Methods: A molecular docking simulation was carried out using an AutoDock Vina program package to estimate the interaction of the ligand-receptor complex. The I-OTB, N-{3-iodo-5-[(2-{[4-(4-methylpiperazin-1-yl)phenyl]aminothieno{3,2-d}pyrimidin-4-yl)oxy]phenyl} acrylamide, was synthesized by introducing an iodine atom in the phenyl group in the 3-aryloxyanilide structure. The half inhibitory concentration (IC50) was determined by employing a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt (WST-8) assay to evaluate the activity of I-OTB. Results: The docking study exhibited that I-OTB could take an interaction similar to that of the parent compound. We successfully synthesized I-OTB and confirmed its structure by instrumental analysis. The binding energy of OTB and I-OTB in complex with EGFR T790M are -8.7 and -7.9 kcal/mol, respectively. The cytotoxicity assay showed that I-OTB also has an affinity towards the EGFR L858R/T790M mutation with the IC50 10.49 ± 5.64 𝜇M compared to the EGFR wild type with the IC50 over than 10 𝜇M. Conclusion: The cytotoxicity effect of I-OTB was comparable to that of OTB. This result indicates that the iodine substituent in OTB did not alter the parent compound selectivity toward double mutations EGFR L858R/T790M. Therefore, I-OTB is prominent for radioiodination, and [123/124I]I-OTB may be a promising candidate for EGFR L858R/T790M mutation imaging.

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A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma

Cited by 8 publications

References 29 publications

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

PRMT-1 and p120-Catenin as EMT Mediators in Osimertinib Resistance in NSCLC

Synthesis and initial in vitro evaluation of olmutinib derivatives as prospective imaging probe for non-small cell lung cancer

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