PDBsum entry 5mo4

Transferase

PDB id: 5mo4

Contents

Protein chain

429 a.a.

Ligands

NIL

AY7

Waters ×307

PDB id:

5mo4

Name:

Transferase

Title:

Abl1 kinase (t334i_d382n) in complex with asciminib and nilotinib

Structure:

Tyrosine-protein kinase abl1. Chain: a. Synonym: abelson murine leukemia viral oncogene homolog 1,abelson tyrosine-protein kinase 1,proto-oncogenE C-abl,p150. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: abl1, abl, jtk7. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.17Å R-factor: 0.184 R-free: 0.217

Authors:

S.W.Cowan-Jacob

Key ref:

A.A.Wylie et al. (2017). The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature, 543, 733-737. PubMed id: 28329763 DOI: 10.1038/nature21702

Date:

13-Dec-16 Release date: 05-Apr-17

Protein chain

P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens

Seq: 1130 a.a.

Struc: 429 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nature21702

Nature 543:733-737 (2017)

PubMed id: 28329763

The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.

A.A.Wylie, J.Schoepfer, W.Jahnke, S.W.Cowan-Jacob, A.Loo, P.Furet, A.L.Marzinzik, X.Pelle, J.Donovan, W.Zhu, S.Buonamici, A.Q.Hassan, F.Lombardo, V.Iyer, M.Palmer, G.Berellini, S.Dodd, S.Thohan, H.Bitter, S.Branford, D.M.Ross, T.P.Hughes, L.Petruzzelli, K.G.Vanasse, M.Warmuth, F.Hofmann, N.J.Keen, W.R.Sellers.

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.