6HD6
ABL1 IN COMPLEX WITH COMPOUND6 AND IMATINIB (STI-571)
Summary for 6HD6
| Entry DOI | 10.2210/pdb6hd6/pdb |
| Related | 6HD4 |
| Descriptor | Tyrosine-protein kinase ABL1, CHLORIDE ION, 3-(morpholin-4-ylmethyl)-~{N}-[4-(trifluoromethyloxy)phenyl]benzamide, ... (5 entities in total) |
| Functional Keywords | phosphotransferase, inhibitor complex, transferase |
| Biological source | Mus musculus (House Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 68890.07 |
| Authors | Cowan-Jacob, S.W. (deposition date: 2018-08-17, release date: 2018-09-12, Last modification date: 2024-05-15) |
| Primary citation | 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 Cited by 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: 30137981DOI: 10.1021/acs.jmedchem.8b01040 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
