6HD4

ABL1 IN COMPLEX WITH COMPOUND 7 AND IMATINIB (STI-571)

6HD4 の概要

• エントリーDOI: 10.2210/pdb6hd4/pdb
• 分子名称: Tyrosine-protein kinase ABL1, GLYCEROL, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: phosphotransferase, inhibitor complex, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69492.59

構造登録者

Cowan-Jacob, S.W. (登録日: 2018-08-17, 公開日: 2018-10-24, 最終更新日: 2024-01-17)

主引用文献

Schoepfer, J.,Jahnke, W.,Berellini, G.,Buonamici, S.,Cotesta, S.,Cowan-Jacob, S.W.,Dodd, S.,Drueckes, P.,Fabbro, D.,Gabriel, T.,Groell, J.M.,Grotzfeld, R.M.,Hassan, A.Q.,Henry, C.,Iyer, V.,Jones, D.,Lombardo, F.,Loo, A.,Manley, P.W.,Pelle, X.,Rummel, G.,Salem, B.,Warmuth, M.,Wylie, A.A.,Zoller, T.,Marzinzik, A.L.,Furet, P.
Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.
J. Med. Chem., 61:8120-8135, 2018

PubMed Abstract: Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

PubMed: 30137981
DOI: 10.1021/acs.jmedchem.8b01040

実験手法

X-RAY DIFFRACTION (2.03 Å)