The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1

Andrew A Wylie, Joseph Schoepfer, Wolfgang Jahnke, Sandra W Cowan-Jacob, Alice Loo, Pascal Furet, Andreas L Marzinzik, Xavier Pelle, Jerry Donovan, Wenjing Zhu, Silvia Buonamici, A Quamrul Hassan, Franco Lombardo, Varsha Iyer, Michael Palmer, Giuliano Berellini, Stephanie Dodd, Sanjeev Thohan, Hans Bitter, Susan BranfordDavid M Ross, Timothy P Hughes, Lilli Petruzzelli, K Gary Vanasse, Markus Warmuth, Francesco Hofmann, Nicholas J Keen, William R Sellers

Research output: Contribution to journalArticlepeer-review

291 Citations (Scopus)

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 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. 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 treatment. 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.

Original languageEnglish
Pages (from-to)733-737
Number of pages5
JournalNature
Volume543
Issue number7647
DOIs
Publication statusPublished or Issued - 30 Mar 2017

Keywords

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Catalytic Domain
  • Cell Proliferation
  • Dasatinib
  • Drug Resistance, Neoplasm
  • Drug Therapy, Combination
  • Fusion Proteins, bcr-abl
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Mice
  • Mutation
  • Niacinamide
  • Pyrazoles
  • Pyrimidines
  • Xenograft Model Antitumor Assays
  • Journal Article

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