Medicinal Chemistry Research

, Volume 27, Issue 6, pp 1666–1678 | Cite as

Selective and novel cyclin-dependent kinases 4 inhibitor: synthesis and biological evaluation

  • Qingxiang Guo
  • Yongtao Li
  • Chao Zhang
  • Zhi Huang
  • Xin Wang
  • Yongwei Nie
  • Yao Li
  • Yanhua Liu
  • Shengyong Yang
  • Rong Xiang
  • Yan Fan
Original Research

Abstract

A series of novel LEE011 derivatives containing pyridine N-oxide were designed, synthesized and evaluated. Systematic study of the structure-activity relationship (SAR) improves the selectivity for CDK4 and led to the identification of compound 9a. The compound showed comparable CDK4 kinase activity with ribociclib and greater selectivity over the closely related CDK6 kinase. The selective CDK4 inhibitor 9a has been demonstrated the antitumor activity via G1 phase cell cycle arrest, as well as dual CDK4/CDK6 inhibitor ribociclib and significantly down-regulated the activity of CDK4-cyclinD-Rb pathway of tumor cells. Taken together, this compound may act as promising lead compound for further development of new CDK4 inhibitors.

Notes

Acknowledgements

This work was supported by the Project of Science and Technology Assistance in Developing Countries (KY201501006) and the National Natural Science Foundation of China (81470354) and the Natural Science Foundation of Tianjin (17JCQNJC13500) and National key scientific research project (2013CB967201).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2180_MOESM1_ESM.docx (744 kb)
Supplementary Information

References

  1. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14:130–146CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chen P, Lee NV, Hu W, Xu M, Ferre RA, Lam H, Bergqvist S, Solowiej J, Diehl W, He Y-A et al. (2016) Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther 15:2273–2281CrossRefPubMedGoogle Scholar
  3. Delano WL (2014) The PyMOL molecular graphics system, version 1.7; Schrödinger LLC, New YorkGoogle Scholar
  4. Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245CrossRefPubMedGoogle Scholar
  5. Fathalla OAE-FM, Ismail MAH, Anwar MM, Abouzid KAM, Ramadan AAK (2013) Novel 2-thiopyrimidine derivatives as CDK2 inhibitors: molecular modeling, synthesis, and anti-tumor activity evaluation. Med Chem Res 22:659–673CrossRefGoogle Scholar
  6. Gao J, Fang C, Xiao Z, Huang L, Chen C-H, Wang L-T, Lee K-H (2015) Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9. MedChemComm 6:444–454CrossRefPubMedGoogle Scholar
  7. Geffken D, Soliman R, FSG Soliman, Abdel-Khalek MM, DAE Issa (2011) Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities. Med Chem Res 20:408–420CrossRefGoogle Scholar
  8. Gonda M, Nieves M, Nunes E, Lopez de Cerain A, Monge A, Lavaggi ML, Gonzalez M, Cerecetto H (2013) Phenazine N,N[prime or minute]-dioxide scaffold as selective hypoxic cytotoxin pharmacophore. Structural modifications looking for further DNA topoisomerase II-inhibition activity. MedChemComm 4:595–607CrossRefGoogle Scholar
  9. Graf F, Mosch B, Koehler L, Bergmann R, Wuest F, Pietzsch J (2010) Cyclin-dependent kinase 4/6 (Cdk4/6) inhibitors: perspectives in cancer therapy and imaging. Mini Rev Med Chem 10:527–539CrossRefPubMedGoogle Scholar
  10. Hamilton E, Infante JR (2016) Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 45:129–138CrossRefPubMedGoogle Scholar
  11. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  12. Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14:2393CrossRefPubMedGoogle Scholar
  13. Hunter T (1997) Oncoprotein networks. Cell 88:333–346CrossRefPubMedGoogle Scholar
  14. Kamal A, Reddy VS, Santosh K, Bharath Kumar G, Shaik AB, Mahesh R, Chourasiya SS, Sayeed IB, Kotamraju S (2014) Synthesis of imidazo[2,1-b][1,3,4]thiadiazole-chalcones as apoptosis inducing anticancer agents. MedChemComm 5:1718–1723CrossRefGoogle Scholar
  15. Kelly MD, Mancera RL (2006) Comparative analysis of the surface interaction properties of the binding sites of CDK2, CDK4, and ERK2. ChemMedChem 1:366–375CrossRefPubMedGoogle Scholar
  16. Lechner M, Lirk P, Rieder J (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol 15:277–289CrossRefPubMedGoogle Scholar
  17. Li C-Q, Wogan GN (2005) Nitric oxide as a modulator of apoptosis. Cancer Lett 226:1–15CrossRefPubMedGoogle Scholar
  18. Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U (2005) Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem 48:737–743CrossRefPubMedGoogle Scholar
  19. Malumbres M, Barbacid M (2001) Milestones in cell division: to cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222–231CrossRefPubMedGoogle Scholar
  20. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153CrossRefPubMedGoogle Scholar
  21. Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291CrossRefPubMedGoogle Scholar
  22. Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602:73PubMedGoogle Scholar
  23. Peyressatre M, Prével C, Pellerano M, Morris MC (2015) Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers 7:179–237CrossRefPubMedPubMedCentralGoogle Scholar
  24. Roskoski Jr R (2016) Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res 107:249–275CrossRefPubMedGoogle Scholar
  25. Sanchez-Martinez C, Gelbert LM, Lallena MJ, de Dios A (2015) Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg Med Chem Lett 25:3420–3435CrossRefPubMedGoogle Scholar
  26. Sarma B, Saikia B, Khatioda R, Bora P (2016) Pyridine N-oxides as coformers in the development of drug cocrystals CrystEngComm 18:8454–8464CrossRefGoogle Scholar
  27. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24:1770–1783CrossRefPubMedGoogle Scholar
  28. Sherr CJ (1996) Cancer cell cycles. Science 274:1672CrossRefPubMedGoogle Scholar
  29. Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T (2005) Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 48:2388–2406CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Qingxiang Guo
    • 1
  • Yongtao Li
    • 1
  • Chao Zhang
    • 1
  • Zhi Huang
    • 1
  • Xin Wang
    • 1
  • Yongwei Nie
    • 1
  • Yao Li
    • 1
  • Yanhua Liu
    • 1
  • Shengyong Yang
    • 2
  • Rong Xiang
    • 1
    • 3
  • Yan Fan
    • 1
    • 4
  1. 1.Department of Medicinal Chemistry, School of MedicineNankai UniversityTianjinChina
  2. 2.Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
  3. 3.2011 Project Collaborative Innovation Center for Biotherapy of Ministry of EducationTianjinChina
  4. 4.Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular RegulationTianjinChina

Personalised recommendations