Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants

Leukemia volume 26, pages 1892–1895 (2012)Cite this article

Subjects

Leukemia is a biologically heterogeneous hematological disease and has become one of the leading causes of cancer-related mortality worldwide.1 Recent studies of the pathogenesis of leukemia have revealed that mutations and/or aberrant expression of specific protein tyrosine kinases, such as FMS-like tyrosine kinase 3 (FLT3) and Abl, are responsible for the development of several common types of leukemia.2, 3, 4 For example, activating mutations in FLT3 are found in approximately 1/3 of acute myeloid leukemia (AML) patients, with the most prevalent activating mutations being ‘internal tandem duplications’ (ITD) in the juxtamembrane domain.5, 6 Several large-scale studies have demonstrated that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis.7, 8, 9 Thus, FLT3 is considered to be an important molecular target in the treatment of AML.

The kinase-inhibition profile of SKLB1028 against a panel of recombinant human protein kinases was measured by the ‘gold standard’ radiometric kinase assay approach, and the results are shown in Supplementary Table S1. SKLB1028 potently inhibited the wild-type and L858R-mutant EGFR with half-maximal inhibitory concentration (IC50) values of 0.031 and 0.004 μM, respectively. The IC50 values of SKLB1028 against FLT3 (Figure 1b) and Abl were 0.055 and 0.081 μM, respectively. Of note, this compound also inhibited the Abl-T315I mutant with considerable potency (IC50: 0.071 μM); this AblT315I mutant is associated with imatinib resistance. Furthermore, SKLB1028 inhibited FYN, HCK, KDR, PDGFRβ, CSF1R, FGFR1 and FGFR2 with moderate activity (the IC50 values were 0.214, 0.487, 0.330, 0.360, 1.040, 1.20 and 0.980 μM, respectively). SKLB1028 displayed negligible inhibitory activity against the 24 additional protein kinases that were tested. These data demonstrate that SKLB1028 is a multikinase inhibitor with high potency against EGFR, FLT3 and Abl and has good kinase-spectrum selectivity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJM, Löwenberg B . MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 2008; 11: 5078–5085.

    Article  Google Scholar 

  2. Tyner JW, Walters DK, Willis SG, Luttropp M, Oost J, Loraux M et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood 2008; 111: 2238–2245.

    Article  CAS  Google Scholar 

  3. Loriaux MM, Levine RL, Tyner JW, Fröhling S, Scholl C, Stoffregen EP et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood 2008; 111: 4788–4796.

    Article  CAS  Google Scholar 

  4. Kantarjian HM, Giles F, Quintás-Cardama AQ, Cortes J . Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res 2007; 13: 1089–1097.

    Article  CAS  Google Scholar 

  5. Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.

    Article  CAS  Google Scholar 

  6. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998; 12: 1333–1337.

    Article  CAS  Google Scholar 

  7. Kiyoi H, Yanada M, Ozekia K . Clinical significance of FLT3 in leukemia. Int J Hematol 2005; 82: 85–92.

    Article  CAS  Google Scholar 

  8. Cloos J, Goemans BF, Hess CJ, Oostveen JW, Waisfisz Q, Corthals S et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 2006; 20: 1217–1220.

    Article  CAS  Google Scholar 

  9. Schlenk RF, Dohner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  Google Scholar 

  10. Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 2006; 108: 3477–3483.

    Article  CAS  Google Scholar 

  11. Knapper S, Mills KI, Gilkes AF, Austin SJ, Walsh V, Burnett AK . The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 2006; 108: 3494–3503.

    Article  CAS  Google Scholar 

  12. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114: 2984–2992.

    Article  CAS  Google Scholar 

  13. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 2008; 22: 915–931.

    Article  CAS  Google Scholar 

  14. Boehrer S, Adès L, Braun T, Galluzzi L, Grosjean J, Fabre C et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 2008; 111: 2170–2180.

    Article  CAS  Google Scholar 

  15. Stegmaier K, Corsello SM, Ross KN, Wong JS, DeAngelo DJ, Golub TR . Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 2005; 106: 2841–2848.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81172987), the National S&T Major Project (2012ZX09102-101-002) and SRFDP (20100181110025).

Author information

Author notes

  1. Z-X Cao, J-J Liu and R-L Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China

    Z-X Cao, J-J Liu, R-L Zheng, J Yang, L Zhong, Y Xu, L-J Wang, C-H Zhang, B-L Wang, S Ma, Z-R Wang, H-Z Xie, Y-Q Wei & S-Y Yang

Authors
  1. Z-X Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R-L Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L-J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C-H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B-L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Z-R Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H-Z Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Y-Q Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S-Y Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S-Y Yang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cao, ZX., Liu, JJ., Zheng, RL. et al. SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants. Leukemia 26, 1892–1895 (2012). https://doi.org/10.1038/leu.2012.67

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.67

This article is cited by

Search

Advanced search

Quick links