New kinase inhibitors that are selectively cytotoxic for tumor cells

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Abstract

To search for substances selectively acting on tumor cells, phenotypic screening in a coculture of tumor cells with non-tumor cells was used in the work. The compound STOCK7S-36520, selectively cytotoxic in the coculture of breast tumor cells MCF7’ and non-tumor MCF10A, contains structural elements characteristic of kinase inhibitors. Analyzing the compound STOCK7S-36520 and its derivative STOCK7S-47016, it turned out that they are new multikinase inhibitors. The highest inhibition of 84% was shown by compound STOCK7S-47016 against GCK kinase. Of interest is the significant selectivity of action against some of the cell lines studied: the selectivity index of STOCK7S-36520 against the prostate tumor cell line PC3 is 29 times compared to the model line of non-tumor fibroblasts VA13.

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About the authors

D. А. Skvortsov

AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Author for correspondence.
Email: skvorratd@mail.ru

Chemistry Department

Russian Federation, Moscow

I. V. Zhirkina

AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Email: skvorratd@mail.ru

Chemistry Department

Russian Federation, Moscow

D. А. Ipatova

AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Email: skvorratd@mail.ru

Chemistry Department

Russian Federation, Moscow

A. R. Pisarev

Higher School of Economics

Email: skvorratd@mail.ru

Faculty of Biology and Biotechnologies

Russian Federation, Moscow

A. S. Malyshev

P. Hertsen Moscow Oncology Research Institute; The Federal State Unitary Enterprise Dukhov Automatics Research Institute

Email: skvorratd@mail.ru
Russian Federation, Moscow; Moscow

Y. A. Ivanenkov

P. Hertsen Moscow Oncology Research Institute; The Federal State Unitary Enterprise Dukhov Automatics Research Institute

Email: skvorratd@mail.ru
Russian Federation, Moscow; Moscow

V. G. Kartsev

InterBioScreen ltd

Email: skvorratd@mail.ru
Russian Federation, Chernogolovka

O. A. Dontsova

AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University; Skolkovo Institute of Science and Technology; Federal State Budgetary Scientific Institution Institute of Bioorganic Chemistry named after Academicians M.M. Shemyakin and Yu.A. Ovchinnikov of the Russian Academy of Sciences

Email: skvorratd@mail.ru

Chemistry Department

Russian Federation, Moscow; Moscow; Moscow

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Supplementary files

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2. Fig. 1. A. The structure of the compound STOCK7S-36520, the pyrimidine-2-amine fragment is shown in green, the amino-2-thiazole fragment is shown in beige. B, C. Cell survival rates from the concentration of the drug in the test in cocultures of A549'_EGFP with VA13_Kat and MCF7'_EGFP with MCF10A_Kat, respectively. The dependences for tumor cells are shown in red, and for etiologically non-tumor cells in yellow.

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3. Fig. 2. A. STOCK7S-47016 structure. B. Example of an image of cells with MCF7'_EGFP tumor cells (green) in co-culture with non-malignant MCF10A_Kat (red) during high-resolution scanning in the FCCT test. 1 – 50 μg/ml STOCK7S-47016; 2 – 12.5 μg/ml STOCK7S-47016; 3 – 2.5 μg/ml STOCK7S-47016; 4 – without the drug. C. Results of the FCCT test for the STOCK7S-47016 drug in the FCCT test in the co-culture of mammary gland cells, the data for tumor cells are marked in red, and for non-tumor cells in yellow.

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4. Fig. 3. Structures of the compounds considered in Table 1.

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5. Fig. 4. Analysis of possible mechanisms of action of drugs on cells. A. Induction of cell death by STOCK7S-47016 (necrosis/apoptosis in A549). B. Inhibition of protein kinases by STOCK7S-36520 and STOCK7S-47016 at 10 μM of the compound and ATP, the kinase activity is normalized to the sample without the inhibitor.

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