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HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance

Leukemia volume 24, pages 1807–1809 (2010)Cite this article

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Imatinib mesylate (STI-571, Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) is now used worldwide for the treatment of chronic myelogenous leukemia (CML) with great success; however, CML often progresses or relapses because of the development of imatinib resistance after long-term treatment. The main cause for imatinib resistance is the acquisition of point mutations in the genetic sequences encoding the Abl kinase domain.1 Therefore, the discovery and development of a new generation of Bcr-Abl inhibitors capable of overriding imatinib resistance is of utmost importance.

To determine whether HH-GV-678 can override imatinib resistance conferred by point mutations in Bcr-Abl, we generated a series of 32D cell lines stably expressing nonmutant Bcr-Abl or the Bcr-Abl mutants Q252H, Y253F, E255K, M351T, H396P and T315I (plasmids kindly provided by Dr Brian Druker, Oregon Health Sciences University, Portland, OR, USA). Consistent with previous findings,2 these Bcr-Abl mutants were resistant to imatinib. HH-GV-678 inhibited the autophosphorylation of imatinib-resistant Bcr-Abl mutants to a similar extent as nonmutated Bcr-Abl (Figure1c and Supplementary Figure 3). However, HH-GV-678 did not inhibit autophosphorylation of a Bcr-Abl T315I mutant expressed in 32D cells (Figure 1d).

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant no. 90813009) and the National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ (Grant no. 2009ZX09102-022).

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  1. Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    H Luo, H Quan, C Xie, Y Xu, L Fu & L Lou

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  1. H Luo
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  2. H Quan
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  3. C Xie
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  5. L Fu
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  6. L Lou
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Correspondence to L Lou.

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Luo, H., Quan, H., Xie, C. et al. HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. Leukemia 24, 1807–1809 (2010). https://doi.org/10.1038/leu.2010.169

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