Skip to main content
SpringerLink
Log in

Type II c-Met inhibitors: molecular insight into crucial interactions for effective inhibition

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein–ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig.1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. https://doi.org/10.3322/caac.21332

    Article  PubMed  Google Scholar 

  2. Collins I, Workman P (2006) New approaches to molecular cancer therapeutics. Nat Chem Biol 2:689–700. https://doi.org/10.1038/nchembio840

    Article  CAS  PubMed  Google Scholar 

  3. Birchmeier C, Gherardi E (1998) Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8:404–410. https://doi.org/10.1016/s0962-8924(98)01359-2

    Article  CAS  PubMed  Google Scholar 

  4. Lv P-C, Yang Y-S, Wang Z-C (2019) Recent progress in the development of small molecule c-met inhibitors. Curr Top Med Chem 19:1276–1288. https://doi.org/10.2174/1568026619666190712205353

    Article  CAS  PubMed  Google Scholar 

  5. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G (2018) Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer 17:45. https://doi.org/10.1186/s12943-018-0796-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M, Huang A, Yang N-y, Nishimura M, Greve J (2013) Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. PNAS USA 110:E2987–E2996. https://doi.org/10.1073/pnas.1302725110

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yuan H, Liu Q, Zhang L, Hu S, Chen T, Li H, Chen Y, Xu Y, Lu T (2018) Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors. Eur J Med Chem 143:491–502. https://doi.org/10.1016/j.ejmech.2017.11.073

    Article  CAS  PubMed  Google Scholar 

  8. Yang Y, Zhang Y, Yang L, Zhao L, Si L, Zhang H, Liu Q, Zhou J (2017) Discovery of imidazopyridine derivatives as novel c-Met kinase inhibitors: Synthesis, SAR study, and biological activity. Bioorg Chem 70:126–132. https://doi.org/10.1016/j.bioorg.2016.12.002

    Article  CAS  PubMed  Google Scholar 

  9. Cui JJ, Shen H, Tran-Dubé M, Nambu M, McTigue M, Grodsky N, Ryan K, Yamazaki S, Aguirre S, Parker M, Li Q, Zou H, Christensen J (2013) Lessons from (S)-6-(1-(6-(1-Methyl-1H-pyrazol-4-yl) [1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats. J Med Chem 56:6651–6665. https://doi.org/10.1021/jm400926x

    Article  CAS  PubMed  Google Scholar 

  10. El-Wakil MH, Ashour HM, Saudi MN, Hassan AM, Labouta IM (2018) Design, synthesis and molecular modeling studies of new series of antitumor 1, 2, 4-triazines with potential c-Met kinase inhibitory activity. Bioorg Chem 76:154–165. https://doi.org/10.1016/j.bioorg.2017.11.006

    Article  CAS  PubMed  Google Scholar 

  11. Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y (2016) Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1, 2-dihydroquinoline scaffold. Bioorg Med Chem Lett 26:4483–4486. https://doi.org/10.1016/j.bmcl.2016.07.077

    Article  CAS  PubMed  Google Scholar 

  12. Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z (2017) Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors. Bioorg Med Chem 25:3195–3205. https://doi.org/10.1016/j.bmc.2017.04.003

    Article  CAS  PubMed  Google Scholar 

  13. Parikh PK, Ghate MD (2018) Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur J Med Chem 143:1103–1138. https://doi.org/10.1016/j.ejmech.2017.08.044

    Article  CAS  PubMed  Google Scholar 

  14. Damghani T, Sedghamiz T, Sharifi S, Pirhadi S (2020) Critical c-Met-inhibitor interactions resolved from molecular dynamics simulations of different c-Met complexes. J Mol Struct 1203:127456. https://doi.org/10.1016/j.molstruc.2019.127456

    Article  CAS  Google Scholar 

  15. Asses Y, Leroux V, Tairi-Kellou S, Dono R, Maina F, Maigret B (2009) Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands. Chem Biol Drug Des 74:560–570. https://doi.org/10.1111/j.1747-0285.2009.00895.x

    Article  CAS  PubMed  Google Scholar 

  16. https://www.playmolecule.org/proteinPrepare/.

  17. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46:W296–W303. https://doi.org/10.1093/nar/gky427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084

    Article  CAS  PubMed  Google Scholar 

  19. Da Silva AWS, Vranken WF (2012) ACPYPE-Antechamber python parser interface. BMC Res notes 5:1–8. https://doi.org/10.1186/1756-0500-5-367

    Article  Google Scholar 

  20. Kumari R, Kumar R, Consortium OSDD, Lynn A (2014) g_mmpbsa-A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54:1951–1962. https://doi.org/10.1021/ci500020m

    Article  CAS  PubMed  Google Scholar 

  21. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. PNAS USA 98:10037–10041. https://doi.org/10.1073/pnas.181342398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Castiglione F, Crupi V, Majolino D, Mele A, Rossi B, Trotta F, Venuti V (2012) Effect of cross-linking properties on the vibrational dynamics of cyclodextrins-based polymers: an experimental–numerical study. J Phys Chem 116:7952–7958. https://doi.org/10.1021/jp303006a

    Article  CAS  Google Scholar 

  23. Brewster ME, Loftsson T (2007) Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev 59:645–666. https://doi.org/10.1016/j.addr.2007.05.012

    Article  CAS  PubMed  Google Scholar 

  24. Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. J Bioinform 29:845–854. https://doi.org/10.1093/bioinformatics/btt055

    Article  CAS  Google Scholar 

  25. Chen K, Kurgan L (2009) Investigation of atomic level patterns in protein—small ligand interactions. PLoS ONE 4:e4473. https://doi.org/10.1371/journal.pone.0004473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aftabuddin M, Kundu S (2007) Hydrophobic, hydrophilic, and charged amino acid networks within protein. Biophys J 93:225–231. https://doi.org/10.1529/biophysj.106.098004

    Article  CAS  PubMed  Google Scholar 

  27. http://manual.gromacs.org/documentation/2019/reference-manual/index.html.

  28. Norman MH, Liu L, Lee M, Xi N, Fellows I, D’Angelo ND, Dominguez C, Rex K, Bellon SF, Kim T-S (2012) Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives. J Med Chem 55:1858–1867. https://doi.org/10.1021/jm201330u

    Article  CAS  PubMed  Google Scholar 

  29. Matsumoto S, Miyamoto N, Hirayama T, Oki H, Okada K, Tawada M, Iwata H, Nakamura K, Yamasaki S, Miki H (2013) Structure-based design, synthesis, and evaluation of imidazo [1, 2-b] pyridazine and imidazo [1, 2-a] pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors. Bioorg Med Chem 21:7686–7698. https://doi.org/10.1016/j.bmc.2013.10.028

    Article  CAS  PubMed  Google Scholar 

  30. Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, Booth RJ, Caldwell TM, Ensinger CL, Hood MM (2015) Altiratinib inhibits tumor growth, invasion, angiogenesis, and microenvironment-mediated drug resistance via balanced inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther 14:2023–2034. https://doi.org/10.1158/1535-7163.MCT-14-1105

    Article  CAS  PubMed  Google Scholar 

  31. Hong DS, LoRusso P, Hamid O, Janku F, Kittaneh M, Catenacci DVT, Chan E, Bekaii-Saab T, Gadgeel SM, Loberg RD, Amore BM, Hwang YC, Tang R, Ngarmchamnanrith G, Kwak EL (2019) Phase I study of AMG 337, a highly selective small-molecule MET inhibitor, in patients with advanced solid tumors. Clin Cancer Res 25:2403. https://doi.org/10.1158/1078-0432.CCR-18-1341

    Article  CAS  PubMed  Google Scholar 

  32. D’Angelo ND, Bellon SF, Booker SK, Cheng Y, Coxon A, Dominguez C, Fellows I, Hoffman D, Hungate R, Kaplan-Lefko P (2008) Design, synthesis, and biological evaluation of potent c-Met inhibitors. J Med Chem 51:5766–5779. https://doi.org/10.1021/jm8006189

    Article  CAS  PubMed  Google Scholar 

  33. Cai Z-W, Wei D, Schroeder GM, Cornelius LA, Kim K, Chen X-T, Schmidt RJ, Williams DK, Tokarski JS, An Y (2008) Discovery of orally active pyrrolopyridine-and aminopyridine-based Met kinase inhibitors. Bioorg Med Chem Lett 18:3224–3229. https://doi.org/10.1016/j.bmcl.2008.04.047

    Article  CAS  PubMed  Google Scholar 

  34. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui Y-H, Huss KL, Konicek BW, Manro JR (2013) LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs 31:833–844. https://doi.org/10.1007/s10637-012-9912-9

    Article  CAS  PubMed  Google Scholar 

  35. Williams DK, Chen X-T, Tarby C, Kaltenbach R, Cai Z-W, Tokarski JS, An Y, Sack JS, Wautlet B, Gullo-Brown J (2010) Design, synthesis and structure–activity relationships of novel biarylamine-based Met kinase inhibitors. Bioorg Med Chem Lett 20:2998–3002. https://doi.org/10.1016/j.bmcl.2010.01.042

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the [Vice Chancellor of Research, Shiraz University of Medical Sciences] under Grant [Number 98-01-12-20089].

Author information

Authors and Affiliations

  1. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Tahereh Damghani, Maryam Elyasi, Somayeh Pirhadi, Zahra Haghighijoo & Somayeh Ghazi

Authors
  1. Tahereh Damghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Elyasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Somayeh Pirhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zahra Haghighijoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Somayeh Ghazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Somayeh Pirhadi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 4824 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Damghani, T., Elyasi, M., Pirhadi, S. et al. Type II c-Met inhibitors: molecular insight into crucial interactions for effective inhibition. Mol Divers 26, 1411–1423 (2022). https://doi.org/10.1007/s11030-021-10267-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-021-10267-7

Keywords

Search

Navigation