5MO4

ABL1 kinase (T334I_D382N) in complex with asciminib and nilotinib

Summary for 5MO4

• Entry DOI: 10.2210/pdb5mo4/pdb
• Descriptor: Tyrosine-protein kinase ABL1, Nilotinib, asciminib, ... (4 entities in total)
• Functional Keywords: kinase, drug, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 1
• Total formula weight: 57162.53

Authors

Cowan-Jacob, S.W. (deposition date: 2016-12-13, release date: 2017-04-05, Last modification date: 2024-05-08)

Primary citation

Wylie, A.A.,Schoepfer, J.,Jahnke, W.,Cowan-Jacob, S.W.,Loo, A.,Furet, P.,Marzinzik, A.L.,Pelle, X.,Donovan, J.,Zhu, W.,Buonamici, S.,Hassan, A.Q.,Lombardo, F.,Iyer, V.,Palmer, M.,Berellini, G.,Dodd, S.,Thohan, S.,Bitter, H.,Branford, S.,Ross, D.M.,Hughes, T.P.,Petruzzelli, L.,Vanasse, K.G.,Warmuth, M.,Hofmann, F.,Keen, N.J.,Sellers, W.R.
The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.
Nature, 543:733-737, 2017

PubMed 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.

PubMed: 28329763
DOI: 10.1038/nature21702

Experimental method

X-RAY DIFFRACTION (2.17 Å)