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The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1

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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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Figure 1: ABL001 is an allosteric inhibitor of BCR–ABL1 that selectively inhibits growth of BCR–ABL1-driven cells.
Figure 2: ABL001 has a resistance profile that is distinct from catalytic-site BCR–ABL1 inhibitors.
Figure 3: The non-overlapping resistance profiles of ABL001 and nilotinib enable durable tumour eradication when used in combination.
Figure 4: Clonal evolution of resistance mutations in a patient treated with ABL001 after previous dasatinib treatment.

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  • 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

Authors and Affiliations

Authors

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.

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Correspondence to Andrew A. Wylie.

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The authors declare no competing financial interests.

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Extended data figures and tables

Extended Data Figure 1 Chemical structure of ABL001 and biophysical characterization of its binding.

a, Chemical structure of ABL001. b, NMR chemical shift assay to determine the location of ABL001 binding. c, NMR-based conformational assay using the resonance of Val525 to monitor the ‘bending’ of helix I in the presence and absence of ABL001. d, Isothermal calorimetry study to determine the binding affinity (Ka) of ABL001 to ABL1.

Extended Data Figure 2 Cellular activity of ABL001 relative to catalytic inhibitors of ABL1.

a, BCR–ABL1 48 h proliferation assay in Ba/F3 cells using a Britelite luciferase detection assay in the presence or absence of IL-3 across a dose range of ABL001 and nilotinib. Each assay was performed in quadruplicate; data are mean ± s.d. b, The sensitivity of KCL-22 cells to ABL001, nilotinib and dasatinib was determined in a 72-h growth assay. Each compound was tested in duplicate. c, KCL-22 cells were incubated with a range of compound concentrations for 1 h and immunoblots run to detect total STAT5 and pSTAT5 (Tyr694), total BCR–ABL1 and pBCR–ABL1 (Tyr245), total CRKL and pCRKL (Tyr207), and GAPDH as a loading control. d, Synergy studies were performed using ABL001 in combination with imatinib, nilotinib or dasatinib. KCL-22 cells were incubated with the compound combinations across a dose range for 72 h, and the level of cell growth relative to DMSO-treated cells was determined.

Extended Data Figure 3 Pharmacokinetics, pharmacodynamics and efficacy of ABL001.

a, Pharmacokinetic (PK) parameters of ABL001 in mouse, rat and dog after a single dose of ABL001. AUC, area under the curve; BA, bioavailability; CL, clearance; Cmax, maximum concentration observed; IV, intravenous; t1/2term, terminal half-life; PO, oral dosing; Tmax, time at maximum concentration; Vss, volume of distribution. b, Total plasma concentrations and levels of pSTAT5 (Tyr694) in fine needle aspirate samples taken from KCL-22 xenografts were monitored after a single oral administration of ABL001 at doses ranging from 3 to 30 mg kg−1. pSTAT5 (Tyr694) levels were determined using a pSTAT5 (Tyr694) meso scale discovery (MSD) assay with each sample run in duplicate; data are mean ± s.d. Samples are expressed as a percentage of the levels of pSTAT5 (Tyr694) before dosing (t = 0). c, ABL001 efficacy in KCL-22 xenograft tumours was assessed by monitoring tumour volume at doses ranging from 3 to 30 mg kg−1 on either a twice a day (BID) or once a day (QD) dosing schedules. Data are mean ± s.e.m. d, ABL001 efficacy in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119 and AL-7155) was assessed by FACS monitoring of the percentage of CD45+ cells per live cell in blood samples taken at varying time points after dosing with either 7.5 mg kg−1 BID (group 2) or 30 mg kg−1 BID (group 3) ABL001 for 3 weeks. A control group (group 1) was treated with PBS vehicle. Data are mean ± s.e.m. (n = 6 per group). e, The tolerability of increasing doses of ABL001 dosed on a BID schedule was determined by monitoring mouse body weight 2–3 times per week. Data are mean ± s.e.m. (n = 5 per group).

Source data

Extended Data Figure 4 Activity of ABL001 and nilotinib in KCL-22 cell clones expressing Thr315Ile and Ala337Val BCR–ABL1 variants.

a, The sensitivity of parental KCL-22 cells (WT) and KCL-22-resistant clones expressing BCR–ABL1 Ala337Val and Thr315Ile mutation variants to treatment with ABL001 (left) and nilotinib (right) was tested in 72 h growth assays. Samples were tested in duplicate; data are mean ± s.d. as a percentage of the vehicle-treated cells. b, KCL-22 Thr315Ile mutant cells were implanted as mouse xenografts and the efficacy of ABL001 across a dose range of 3–30 mg kg−1 BID was determined. Nilotinib was tested at 75 mg kg−1 BID as a control. Data are mean ± s.e.m. (n = 7 per group). T/C denotes ratio of tumour volume in control versus treated mice; ‘Reg’ denotes regression.

Source data

Extended Data Table 1 Activity of ABL001 in biochemical assays

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This file contains the Supplementary Methods, Supplementary Table and the uncropped blots. (PDF 1954 kb)

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Wylie, A., Schoepfer, J., Jahnke, W. et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature 543, 733–737 (2017). https://doi.org/10.1038/nature21702

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