3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo

Klemt I, Varzatskii O, Selin R, Vakarov S, Kovalska VB, Bila G, Bilyy R, Voloshin Y, Cossío Cuartero I, Hidalgo A, Frey B, Becker I, Friedrich B, Tietze R, Friedrich RP, Alexiou C, Ursu EL, Rotaru A, Solymosi I, Perez-Ojeda Rodriguez ME, Mokhir A (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of the American Chemical Society American Chemical Society

Pages Range: 22252–22264

DOI: 10.1021/jacs.3c08827

Abstract

The amount of unfolded proteins is increased in cancer cells, leading to endoplasmic reticulum (ER) stress. Therefore, cancer cells are sensitive to drugs capable of further enhancing ER stress. Examples of such drugs include the clinically approved proteosome inhibitors bortezomib and carfilzomib. Unfortunately, the known ER stress inducers exhibit dose-limiting side effects that justify the search for better, more cancer-specific drugs of this type. Herein, we report on FeC 2, which binds to unfolded proteins prevents their further processing, thereby leading to ER stress and ROS increase in cancer cells, but not in normal cells. FeC 2 exhibits low micromolar toxicity toward human acute promyelocytic leukemia HL-60, Burkitt’s lymphoma BL-2, T-cell leukemia Jurkat, ovarian carcinoma A2780, lung cancer SK-MES-1, and murine lung cancer LLC1 cells. Due to the cancer-specific mode of action, 2 is not toxic in vivo up to the dose of 147 mg/kg, does not affect normal blood and bone marrow cells at the therapeutically active dose, but strongly suppresses both primary tumor growth (confirmed in Nemeth-Kellner lymphoma and LLC1 lung cancer models of murine tumor) and spreading of metastases (LLC1).

Authors with CRIS profile

Insa Klemt Lehrstuhl für Organische Chemie II Roman Selin Lehrstuhl für Organische Chemie II Benjamin Frey Department of Radiation Oncology Ina Becker Department of Radiation Oncology Bernhard Friedrich Department of Otorhinolaryngology – Head and Neck Surgery Rainer Tietze Department of Otorhinolaryngology – Head and Neck Surgery Christoph Alexiou Professur für Nanomedizin Iris Solymosi Lehrstuhl für Organische Chemie II Maria Eugenia Perez-Ojeda Rodriguez Lehrstuhl für Organische Chemie II Andriy Mokhir Professur für Organische Chemie

Involved external institutions

Princeton BioMolecular Research, Inc. US United States (USA) (US) "Petru Poni" Institute of Macromolecular Chemistry RO Romania (RO) A.N.Nesmeyanov Institute of Organoelement Compounds (INEOS RAS) / Институт элементоорганических соединений Российской Академии Наук им. А.Н. Несмеянова (ИНЭОС РАН) RU Russian Federation (RU) Danylo Halytsky Lviv National Medical University / Львiвський Національний Медичний Унiверситет iм. Данила Галицького UA Ukraine (UA) Spanish National Center for Cardiovascular Research / Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) ES Spain (ES) Vernadsky Institute of general and inorganic chemistry / Інститут загальної та неорганічної хімії імені В. I. Вернадського НАН України UA Ukraine (UA)

How to cite

APA:

Klemt, I., Varzatskii, O., Selin, R., Vakarov, S., Kovalska, V.B., Bila, G.,... Mokhir, A. (2023). 3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo. Journal of the American Chemical Society, 22252–22264. https://doi.org/10.1021/jacs.3c08827

MLA:

Klemt, Insa, et al. "3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In Vivo." Journal of the American Chemical Society (2023): 22252–22264.

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