New kinase inhibitors that are selectively cytotoxic for tumor cells

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

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.

Full Text

Restricted Access

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

References

  1. Jaffee, E.M., C.V. Dang, D.B. Agus, et al., Future cancer research priorities in the USA: a Lancet Oncology Commission // Lancet Oncol, 2017. 18(11): P. e653–e706.
  2. Seebacher, N.A., A.E. Stacy, G.M. Porter, et al., Clinical development of targeted and immune based anti-cancer therapies. // J Exp Clin Cancer Res, 2019. 38(1): P. 156.
  3. Levitzki, A. and S. Klein, My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer. // Proc Natl Acad Sci USA, 2019. 116(24): P. 11579–11586.
  4. Sadri, A., Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs // J Med Chem, 2023. 66(18): P. 12651–12677.
  5. Ediriweera, M.K., K.H. Tennekoon, and S.R. Samarakoon, In vitro assays and techniques utilized in anticancer drug discovery. // J Appl Toxicol, 2019. 39(1): P. 38–71.
  6. Cagan, R., Drug screening using model systems: some basics. // Dis Model Mech, 2016. 9(11): P. 1241–1244.
  7. Spink, B.C., R.W. Cole, B.H. Katz, et al., Inhibition of MCF-7 breast cancer cell proliferation by MCF-10A breast epithelial cells in coculture. // Cell Biol Int, 2006. 30(3): P. 227–38.
  8. Skvortsov, D.A., M.A. Kalinina, I.V. Zhirkina, et al., From Toxicity to Selectivity: Coculture of the Fluorescent Tumor and Non-Tumor Lung Cells and High-Throughput Screening of Anticancer Compound. // Front. Pharmacol., 2021. 12: P. 1–11.
  9. Xing, L., J. Klug-Mcleod, B. Rai, et al., Kinase hinge binding scaffolds and their hydrogen bond patterns. // Bioorg Med Chem, 2015. 23(19): P. 6520–7.
  10. Cohen, P., D. Cross, and P.A. Janne, Kinase drug discovery 20 years after imatinib: progress and future directions. // Nat Rev Drug Discov, 2021. 20(7): P. 551–569.
  11. Kalinina, M.A., D.A. Skvortsov, M.P. Rubtsova, et al., Cytotoxicity Test Based on Human Cells Labeled with Fluorescent Proteins: Fluorimetry, Photography, and Scanning for High-Throughput Assay. // Mol Imaging Biol, 2018. 20(3): P. 368–377.
  12. Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays // J Immunol Methods, 1983. 65(1-2): P. 55–63.
  13. Brenchley, G., L.j. Farmer, E.M. Harrington, et al. Thiazoles useful as inhibitors of protein kinases.2003 Last Update [cited Access 2003; Edition:[Description].
  14. Andersen, C.B., Y. Wan, J.W. Chang, et al., Discovery of selective aminothiazole aurora kinase inhibitors. // ACS Chem Biol, 2008. 3(3): P. 180–92.
  15. Skvortsov, D., I. Zhirkina, M. Kalinina, et al. Application of indenofluorene derivative for inhibition and/or elimination of tumor cells.2023 Last Update [cited Access 2023; Edition:[Description].
  16. Weisberg, E., P. Manley, J. Mestan, et al., AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. // Br J Cancer, 2006. 94(12): P. 1765–9.
  17. Manley, P.W., P. Drueckes, G. Fendrich, et al., Extended kinase profile and properties of the protein kinase inhibitor nilotinib. // Biochim Biophys Acta, 2010. 1804(3): P. 445–53.
  18. Tsherniak, A., F. Vazquez, P.G. Montgomery, et al., Defining a Cancer Dependency Map. // Cell, 2017. 170(3): P. 564-576 e16.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
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.

Download (52KB)
Indexing metadata
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.

Download (67KB)
Indexing metadata
4. Fig. 3. Structures of the compounds considered in Table 1.

Download (82KB)
Indexing metadata
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.

Download (59KB)
Indexing metadata

Copyright (c) 2025 Russian Academy of Sciences