The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1

  • Nature. 2017 Mar 30;543(7647):733-737. doi: 10.1038/nature21702.
Andrew A Wylie  1 ,  Joseph Schoepfer  2 ,  Wolfgang Jahnke  2 ,  Sandra W Cowan-Jacob  2 ,  Alice Loo  1 ,  Pascal Furet  2 ,  Andreas L Marzinzik  2 ,  Xavier Pelle  2 ,  Jerry Donovan  1 ,  Wenjing Zhu  1 ,  Silvia Buonamici  1 ,  A Quamrul Hassan  1 ,  Franco Lombardo  1 ,  Varsha Iyer  2 ,  Michael Palmer  1 ,  Giuliano Berellini  1 ,  Stephanie Dodd  1 ,  Sanjeev Thohan  1 ,  Hans Bitter  1 ,  Susan Branford  3 ,  David M Ross  4 ,  Timothy P Hughes  5 ,  Lilli Petruzzelli  1 ,  K Gary Vanasse  1 ,  Markus Warmuth  1 ,  Francesco Hofmann  2 ,  Nicholas J Keen  1 ,  William R Sellers  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
  • 2. Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 3. Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
  • 4. Haematology Directorate, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia.
  • 5. South Australian Health &Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
PMID: 28329763 DOI: 10.1038/nature21702
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.

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