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Abstract

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years1. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML2. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment3,4. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

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Change history

  • 29 March 2017

    In the key to Figure 3b, ‘CME911’ was replaced with ‘ABL001’.

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Acknowledgements

The authors wish to thank the entire team who contributed to the discovery and development of ABL001.

Author information

Author notes

    • Silvia Buonamici
    •  & Markus Warmuth

    Present addresses: H3 Biomedicine Target Biology, 300 Technology Square, Cambridge, Massachusetts 02139, USA.

Affiliations

  1. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA

    • Andrew A. Wylie
    • , Alice Loo
    • , Jerry Donovan
    • , Wenjing Zhu
    • , Silvia Buonamici
    • , A. Quamrul Hassan
    • , Franco Lombardo
    • , Michael Palmer
    • , Giuliano Berellini
    • , Stephanie Dodd
    • , Sanjeev Thohan
    • , Hans Bitter
    • , Lilli Petruzzelli
    • , K. Gary Vanasse
    • , Markus Warmuth
    • , Nicholas J. Keen
    •  & William R. Sellers
  2. Novartis Institutes for BioMedical Research, Basel, Switzerland

    • Joseph Schoepfer
    • , Wolfgang Jahnke
    • , Sandra W. Cowan-Jacob
    • , Pascal Furet
    • , Andreas L. Marzinzik
    • , Xavier Pelle
    • , Varsha Iyer
    •  & Francesco Hofmann
  3. Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia

    • Susan Branford
  4. Haematology Directorate, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia

    • David M. Ross
  5. South Australian Health & Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia

    • Timothy P. Hughes

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Contributions

A.A.W., J.D., W.Z., S.Bu., A.Q.H. and M.P. directed or performed cell signalling, enzymology and/or genetic characterization work. J.S., A.L.M. and X.P. directed or performed medicinal chemistry work. W.J., S.W.C.-J. and P.F. directed or performed structural biology, NMR and/or structural modelling and cheminformatics analysis. A.A.W., A.L., S.Bu., F.L., V.I., G.B., S.D. and S.T. directed or analysed in vivo pharmacology, pharmacokinetic, formulation and/or safety studies. H.B. performed mathematical modelling. K.G.V., S.Br., D.M.R. and T.P.H. were responsible for clinical strategy and/or investigations. L.P., M.W., F.H., N.J.K. and W.R.S. contributed to overall project oversight and strategy. A.A.W. and W.R.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andrew A. Wylie.

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DOI

https://doi.org/10.1038/nature21702

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