Skip to main content
SpringerLink
Log in

Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

  • Published:
Pharmaceutical Chemistry Journal Aims and scope

A series of new 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)-maleimides were synthesized and evaluated for their inhibitory activity against IDH1-R132H. Most compounds exhibited significant potency to IDH1-R132H inhibition. Among these, 3-(1-(3-(1H-imidazol-1-yl)propyl)-6-bromo-1H-indol-3-yl)-4-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-pyrrole-2,5-dione (compound IXb), was the most promising IDH1-R132H inhibitor (IC50 = 0.031 μM) and could significantly inhibit the production of 2-HG in U87MG IDH1-R132H cells. Preliminary structure–activity relationships and molecular modeling studies are discussed based on the experimental data obtained.

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.
Scheme 2.
Fig. 2.
Fig. 3.

Similar content being viewed by others

References

  1. L. Dang, D. W. White, S. Gross, et al., Nature, 462, 739 – 744 (2009).

    Article  CAS  Google Scholar 

  2. I. Kos and I. Batiniæhaberle, New Engl. J. Med., 360, 765 – 773 (2009).

    Article  Google Scholar 

  3. L. Dang, S. Jin, and S. M. Su, Trends Mol. Med., 16, 387 – 397 (2010).

    Article  CAS  Google Scholar 

  4. A. Green and P. Beer, New Engl. J. Med., 362, 369 – 370 (2010).

    Article  CAS  Google Scholar 

  5. H. W. Kao, D. C. Liang, J. H. Wu, et al., Neoplasia, 16, 481 – 488 (2014).

    Article  CAS  Google Scholar 

  6. S. Gross and R. M. Cairns, J. Exp. Med., 207, 339 – 344 (2010).

    CAS  Google Scholar 

  7. Y. Zhang, H.Wei, K. Tang, et al., Genet. Test. Mol. Biomarkers, 16, 991 – 995 (2012).

    Article  CAS  Google Scholar 

  8. C. C. Lin, H. A. Hou, W. C. Chou, et al., Am. J. Hematol., 89, 137 – 144 (2014).

    Article  CAS  Google Scholar 

  9. M. M. Patnaik, C. A. Hanson, J. M. Hodnefield, et al., Leukemia, 26, 101 – 105 (2012).

    Article  CAS  Google Scholar 

  10. A. F. Ghiam, R. A. Cairns, J. Thoms, et al., Oncogene, 31, 3826 (2010).

    Article  Google Scholar 

  11. M. K. Kaneko, X. Liu, H. Oki, et al., Cancer Sci., 105, 744 – 748 (2014).

    Article  Google Scholar 

  12. A. R. Grassian, R. Pagliarini. and D. Y. Chiang, Curr. Opin. Gastroenterol., 30, 295 – 302 (2014).

  13. H. Yang, D. Ye, K. Guan, and Y. Xiong, Clin. Cancer Res., 18, 5562 – 5571 (2012).

    Article  CAS  Google Scholar 

  14. W. Xu, H. Yang, Y. Liu, et al., Cancer Cell, 19, 17 – 30 (2011).

    Article  CAS  Google Scholar 

  15. Y. S. Cho, J. R. Levell, G. Liu, et al., ACS Med. Chem. Lett., 8, 1116 – 1121 (2017).

    Article  CAS  Google Scholar 

  16. G. Deng, J. Shen, M. Yin, et al., J. Biol. Chem., 290, 762 – 774 (2015).

    Article  CAS  Google Scholar 

  17. Y. Y. Hu, A. H. Gao, H. Liao, et al., Arch. Pharm. (2018); https://doi.org/10.1002/ardp.201800039.

  18. X. Q. Liu, Y. Y. Hu, A. H. Gao, et al., Bioorg. Med. Chem. (2018); https://doi.org/10.1016/j.bmc.2018.12.029.

  19. U. C. Okoye-Okafor, B. Bartholdy, J. Cartier, et al., Nature Chem. Biol., 11, 878 – 886 (2015).

    Article  CAS  Google Scholar 

  20. D. Rohle, J. Popovici-Muller, N. Palaskas, et al., Science, 340, 626 – 630 (2013).

    Article  CAS  Google Scholar 

  21. F. Wu, H. Jiang, B. Zheng, et al., J. Med. Chem., 58, 6899 – 6908 (2015).

    Article  CAS  Google Scholar 

  22. Q. Ye, Y. Shen, Y. B. Zhou, et al., Eur. J. Med. Chem., 68, 361 – 371 (2013).

    Article  CAS  Google Scholar 

  23. Q. Ye, G. Q. Xu, D. Lv, et al., Biorg. Med. Chem., 17, 4302 – 4312 (2009).

    Article  CAS  Google Scholar 

  24. B. Tan, Z. H. Lu, S. C. Dong, et al., Anal. Biochem., 465, 134 – 147 (2014).

    Article  CAS  Google Scholar 

  25. P. S. Ward, J. Patel, D. R. Wise, et al., Cancer Cell, 17, 225 – 234 (2010).

    Article  CAS  Google Scholar 

  26. H. Noushmehr, D. J. Weisenberger, K. Diefes, et al. Cancer Cell, 17, 510 – 522 (2010).

    Article  CAS  Google Scholar 

  27. R. Chowdhury, K. K. Yeoh, Y. M. Tian, et al., EMBO Rep., 12, 463 – 469 (2011).

    Article  CAS  Google Scholar 

  28. M. E. Figueroa, O. Abdel-Wahab, C. Lu, et al., Cancer Cell, 18, 553 – 567 (2010).

    Article  CAS  Google Scholar 

  29. M. Ko, Y. Huang, A. M. Jankowska, et al., Nature, 468, 839 – 843 (2010).

    Article  CAS  Google Scholar 

  30. J-A Losman, R. E. Looper, P. Koivunen, et al., Science, 339, 1621 – 1625 (2013).

    Article  CAS  Google Scholar 

  31. S. Zhao, Y. Lin, W. Xu, et al., Science, 324, 261 – 265 (2009).

    Article  CAS  Google Scholar 

  32. S. Jones, J. Ahmet, K. Ayton, et al., J. Med. Chem., 59, 11120 – 11137 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the Natural Science Foundation of Zhejiang (LY18H300009), the Postdoctoral Science Foundation of China (2014M550256), the State Key Laboratory of Drug Research (SIMM1601KF-04), National Natural Science Foundation of China (8150131067), “Personalized Medicines-Molecular Signature-based Drug Discovery and Development,” Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020328).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Author information

Author notes

  1. Jianghong Xu, Yuanyuan Hu and Xiaoqi Liu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310032, China

    Jianghong Xu, Yuanyuan Hu, Xiaoqi Liu, Jianrong Gao & Qing Ye

  2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Anhui Gao, Lixin Gao, Lei Xu, Yubo Zhou & Ji Li

  3. College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, China

    Chunqi Hu

Authors
  1. Jianghong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuanyuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoqi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anhui Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lixin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yubo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jianrong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qing Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chunqi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ji Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qing Ye.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, J., Hu, Y., Liu, X. et al. Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors. Pharm Chem J 55, 655–664 (2021). https://doi.org/10.1007/s11094-021-02475-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11094-021-02475-0

Keywords

Search

Navigation