Binding of the antibacterial drug clofoctol and analogues to the Cdc7/Dbf4 kinase complex. A computational study

  • Gérard Vergoten University of Lille, Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France
  • Christian Bailly OncoWitan, Lille (Wasquehal), 59290, France
Keywords: Clofoctol, Cdc7 kinase, Antibacterial drug, Cancer therapeutic, Drug-protein binding, Molecular modelling

Abstract

Drugs targeting the cell division cycle kinase 7 (Cdc7) are actively searched for the treatment of different pathologies such as amyotrophic lateral sclerosis and cancer. Cdc7 interacts with multiple protein partners, including protein Dbf4 to form the Dbf4-dependent kinase (DDK) complex which regulates DNA replication initiation. Cdc7 and its activator Dbf4 are over-expressed in some cancers. The antibacterial drug clofoctol (CFT), used to treat respiratory tract infections, has been shown to block Cdc7 kinase activity, acting as a non-ATP-competitive inhibitor, capable of arresting DNA synthesis in cancer cells. We have modeled the interaction of CFT with the DDK complex and identified four potential binding sites at the interface of the Cdc7/Dbf4 heterodimer: at T109 and D128 (Cdc7), V220 and I330 (Dbf4). CFT behaves as an interfacial protein-protein inhibitor of the Cdc7/Dbf4 complex, limiting drug access to the proximal kinase site. Six CFT analogues have been tested for binding to the kinase complex. Two potent binders were analyzed in detail. The CFT structure was modulated to replace the two chlorine atoms with hydroxyl groups. The empirical potential energy of interaction (ΔE) calculated with hydroxylated compounds points to a more favorable interaction with the DDK complex, in particular at D128 site with the compound bearing two ortho-OH groups. Our work contributes to the identification of novel DDK inhibitors.

DOI: http://dx.doi.org/10.5281/zenodo.5527211

Downloads

Download data is not yet available.

References

1. Rojas-Prats E, Martinez-Gonzalez L, Gonzalo-Consuegra C, Liachko NF, Perez C, Ramírez D, et al. Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis. Eur J Med Chem. 2020; 210: 112968.
2. Vaca G, Martinez-Gonzalez L, Fernandez A, Rojas-Prats E, Porras G, Cuevas EP, Gil C, et al. Therapeutic potential of novel Cell Division Cycle Kinase 7 inhibitors on TDP-43-related pathogenesis such as Frontotemporal Lobar Degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). J Neurochem. 2020; 156: 379-390.
3. Yang CC, Kato H, Shindo M, Masai H. Cdc7 activates replication checkpoint by phosphorylating the Chk1-binding domain of Claspin in human cells. Elife. 2019; 8: 50796.
4. Parri E, Kuusanmäki H, van Adrichem AJ, Kaustio M, Wennerberg K. Identification of novel regulators of STAT3 activity. PLoS One. 2020; 15: 0230819.
5. Ito S, Goto H, Kuniyasu K, Shindo M, Yamada M, Tanaka K, et al. Cdc7 kinase stimulates Aurora B kinase in M-phase. Sci Rep. 2019; 9: 18622.
6. Rainey MD, Quinlan A, Cazzaniga C, Mijic S, Martella O, Krietsch J, et al. CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage. EMBO Rep. 2020; 21: 48920.
7. Montagnoli A, Moll J, Colotta F. Targeting cell division cycle 7 kinase: a new approach for cancer therapy. Clin Cancer Res. 2010; 16: 4503-4508.
8. Yamada M, Masai H, Bartek J. Regulation and roles of Cdc7 kinase under replication stress. Cell Cycle. 2014;13:1859-1866.
9. Jin S, Ma H, Yang W, Ju H, Wang L, Zhang Z. Cell division cycle 7 is a potential therapeutic target in oral squamous cell carcinoma and is regulated by E2F1. J Mol Med. 2018; 96: 513-525.
10. Gad SA, Ali HEA, Gaballa R, Abdelsalam RM, Zerfaoui M, Ali HI, et al. Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway. Sci Rep. 2019; 9: 14197.
11. Iwai K, Nambu T, Dairiki R, Ohori M, Yu J, Burke K, et al. Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor. Sci Adv. 2019; 5: 3660.
12. Kurasawa O, Miyazaki T, Homma M, Oguro Y, Imada T, Uchiyama N, et al. Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent. J Med Chem. 2020; 63: 1084-1104.
13. Erbayraktar Z, Alural B, Erbayraktar RS, Erkan EP. Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness. Cancer Cell Int. 2016; 16: 88.
14. O' Reilly E, Dhami SPS, Baev DV, Ortutay C, Halpin-McCormick A, Morrell R, et al. Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML. Sci Rep. 2018; 8: 15752.
15. McLaughlin RP, He J, van der Noord VE, Redel J, Foekens JA, Martens JWM, et al. A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy. Breast Cancer Res. 2019; 21: 77.
16. Chen EW, Tay NQ, Brzostek J, Gascoigne NRJ, Rybakin V. A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation. Front Immunol. 2019; 10: 1718.
17. Irie T, Asami T, Sawa A, Uno Y, Hanada M, Taniyama C, et al. Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors. Eur J Med Chem. 2017; 130: 406-418.
18. Koltun ES, Tsuhako AL, Brown DS, Aay N, Arcalas A, Chan V, et al. Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012; 22: 3727-3731.
19. Sasi NK, Tiwari K, Soon FF, Bonte D, Wang T, Melcher K, et al. The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PLoS One. 2014; 9: 113300.
20. Jin SF, Ma HL, Liu ZL, Fu ST, Zhang CP, He Y. XL413, a cell division cycle 7 kinase inhibitor enhanced the anti-fibrotic effect of pirfenidone on TGF-beta1-stimulated C3H10T1/2 cells via Smad2/4. Exp Cell Res. 2015; 339: 289-299.
21. Dick SD, Federico S, Hughes SM, Pye VE, O'Reilly N, Cherepanov P. Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase. Structure. 2020; 28: 954-962.
22. Ngo M, Wechter N, Tsai E, Shun TY, Gough A, Schurdak ME, et al. A High-Throughput Assay for DNA Replication Inhibitors Based upon Multivariate Analysis of Yeast Growth Kinetics. SLAS Discov. 2019; 24: 669-681.
23. Wienert B, Nguyen DN, Guenther A, Feng SJ, Locke MN, Wyman SK, et al. Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair. Nat Commun. 2020; 11: 2109.
24. Larasati, Duncker BP. Mechanisms Governing DDK Regulation of the Initiation of DNA Replication. Genes (Basel) 2016; 8: 3.
25. Cheng AN, Lo YK, Lin YS, Tang TK, Hsu CH, Hsu JT, Lee AY. Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach. EBioMedicine. 2018; 36: 241-251.
26. Bailly C, Vergoten G. A new horizon for the old antibacterial drug clofoctol. Drug Discov Today. 2021; 26: 1302-1310.
27. Jorgensen WL, Tirado-Rives J. Molecular modeling of organic and biomolecular systems using BOSS and MCPRO. J Comput Chem. 2005; 26: 1689-1700.
28. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997; 267: 727-748.
29. Vergoten G, Mazur I, Lagant P, Michalski JC, Zanetta JP. The SPASIBA force field as an essential tool for studying the structure and dynamics of saccharides. Biochimie. 2003; 85: 65-73.
30. Lagant P, Nolde D, Stote R, Vergoten G, Karplus M. Increasing Normal Modes Analysis Accuracy: The SPASIBA Spectroscopic Force Field Introduced into the CHARMM Program. J Phys Chem A. 2004; 108: 4019-4029.
31. Amoros M, Sauvager F, Vachy R. 1993. Therapeutic composition containing a phenol compound and propolis useful against lipidic capside viruses, especially the herpes viruses. EP0521906A1/US-6153226-A/WO-9113626-A1.
32. Rainey MD, Quachthithu H, Gaboriau D, Santocanale C. DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors. ACS Chem Biol. 2017; 12: 1893-1902.
33. Cao JX, Lu Y. Targeting CDC7 improves sensitivity to chemotherapy of esophageal squamous cell carcinoma. Onco Targets Ther. 2018; 12: 63-74.
34. Makhouri FR, Ghasemi JB. High-throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7. Mol Inform. 2018; 37: 1800022.
35. Zhao C, Tovar C, Yin X, Xu Q, Todorov IT, Vassilev LT, Chen L. Synthesis and evaluation of pyrido-thieno-pyrimidines as potent and selective Cdc7 kinase inhibitors. Bioorg Med Chem Lett. 2009; 19: 319-323.
36. Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A, et al. First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009; 52: 293-307.
37. Swords R, Mahalingam D, O'Dwyer M, Santocanale C, Kelly K, Carew J, Giles F. Cdc7 kinase - a new target for drug development. Eur J Cancer. 2010; 46: 33-40.
Published
2021-09-24
How to Cite
(1)
Vergoten, G.; Bailly, C. Binding of the Antibacterial Drug Clofoctol and Analogues to the Cdc7/Dbf4 Kinase Complex. A Computational Study. European Journal of Biological Research 2021, 11, 446-457.
Section
Research Articles