Rociletinib analog for double mutation non-small cell lung cancer

Excerpt:


J. Pharm. Pharmacogn. Res., vol. 12, no. 2, pp. 231-242, Mar-Apr 2024. DOI: https://doi.org/10.56499/jppres23.1743_12.2.231 Original Article Synthesis and evaluation of a rociletinib analog as prospective imaging double mutation L858R/T790M in non-small cell lung cancer [Síntesis y evaluación de un análogo de rociletinib como imagen prospectiva de la doble mutación L858R/T790M en cáncer de pulmón no … Continue reading Rociletinib analog for double mutation non-small cell lung cancer

J. Pharm. Pharmacogn. Res., vol. 12, no. 2, pp. 231-242, Mar-Apr 2024.

DOI: https://doi.org/10.56499/jppres23.1743_12.2.231

Original Article

Synthesis and evaluation of a rociletinib analog as prospective imaging double mutation L858R/T790M in non-small cell lung cancer

[Síntesis y evaluación de un análogo de rociletinib como imagen prospectiva de la doble mutación L858R/T790M en cáncer de pulmón no microcítico]

Muammar Fawwaz1,2*, Kenji Mishiro3**, Bambang Purwono4***, Ryuichi Nishii5, Kazuma Ogawa2,3

1Faculty of Pharmacy, Universitas Muslim Indonesia, Urip Sumoharjo KM. 5, Makassar 90-231, Indonesia.

2Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

3Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

4Laboratory of Organic Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia.

5Biomedical Imaging Sciences, Department of Integrated Health Sciences, Graduate School of Medicine, Nagoya University, Japan.

*E-mail: *muammar.fawwaz@umi.ac.id;  **mishiro@p.kanazawa-u.ac.jp;  ***purwono.bambang@ugm.ac.id

Abstract

Context: Imaging the mutation status of non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitor (TKI) analogs has garnered interest due to their unique interactions with the target epidermal growth factor receptor (EGFR). Rociletinib is a third-generation TKI that selectively inhibits the activated EGFR L858R/T790M mutations while sparing the wild-type EGFR.

Aims: To synthesize a rociletinib analog for radioiodination purposes and evaluate its affinity for EGFR L858R/T790M using molecular docking and in vitro cytotoxicity assay.

Methods: The rociletinib analog, N-{3-[(4-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-2-yl)amino] -5-iodophenyl} acrylamide (I-RMFZ), was produced by adding iodine into the diaminophenyl group and changing the position of the trifluoromethyl group. A simulation of molecular docking was conducted using the AutoDock Vina software suite. IC50 of I-RMFZ was determined using a cell cytotoxicity assay.

Results: I-RMFZ was successfully synthesized through multistep reactions. Molecular docking revealed that I-RMFZ interacts with the EGFR L858R/T790M mutation. Cytotoxicity assay demonstrated that I-RMFZ had a high selectivity towards EGFR L858R/T779M mutation.

Conclusions: I-RMFZ is notable for radioiodination and is anticipated to be comparable with in vivo features of rociletinib. Thus, I-RMFZ can potentially be developed as an imaging agent for NSCLC through preclinical assay.

Keywords: acrylamide; carcinoma; epidermal growth factor; molecular docking simulation; mutation.

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Resumen

Contexto: La obtención de imágenes del estado de la mutación del cáncer de pulmón no microcítico (CPNM) utilizando análogos radiomarcados de inhibidores de la tirosina cinasa (TKI) ha despertado interés debido a sus interacciones únicas con el receptor del factor de crecimiento epidérmico (EGFR) diana. El rociletinib es un TKI de tercera generación que inhibe selectivamente las mutaciones activadas L858R/T790M del EGFR, mientras que no afecta al EGFR de tipo salvaje.

Objetivos: Sintetizar un análogo de rociletinib con fines de radioiodinación y evaluar su afinidad por EGFR L858R/T790M mediante acoplamiento molecular y ensayo de citotoxicidad in vitro.

Métodos: El análogo de rociletinib, N-{3-[(4-{[4-(4-acetilpiperazin-1-il)-2-metoxifenil]amino}-5-(trifluorometil)pirimidin-2-il)amino] -5-yodofenil}acrilamida (I-RMFZ), se produjo añadiendo yodo al grupo diaminofenil y cambiando la posición del grupo trifluorometil. Se realizó una simulación de acoplamiento molecular utilizando el paquete de software AutoDock Vina. El IC50 de I-RMFZ se determinó mediante un ensayo de citotoxicidad celular.

Resultados: I-RMFZ se sintetizó con éxito mediante reacciones de múltiples pasos. El acoplamiento molecular reveló que I-RMFZ interacciona con la mutación L858R/T790M del EGFR. El ensayo de citotoxicidad demostró que I-RMFZ tenía una alta selectividad hacia la mutación L858R/T779M del EGFR.

Conclusiones: I-RMFZ destaca por su radioiodinación y se prevé que sea comparable con las características in vivo de rociletinib. Así pues, I-RMFZ puede desarrollarse potencialmente como agente de imagen para CPNM mediante ensayo preclínico.

Palabras Clave: acrilamida; carcinoma; factor de crecimiento epidérmico; simulación de acoplamiento molecular; mutación.

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Citation Format: Fawwaz M, Mishiro K, Purwono B, Nishii R, Ogawa K (2024) Synthesis and evaluation of a rociletinib analog as prospective imaging double mutation L858R/T790M in non-small cell lung cancer. J Pharm Pharmacogn Res 12(2): 231–242. https://doi.org/10.56499/jppres23.1743_12.2.231
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