4U0I

Crystal structure of KIT in complex with ponatinib

Summary for 4U0I

• Entry DOI: 10.2210/pdb4u0i/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: kit, receptor tyrosine kinase, inhibitor, ponatinib, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Isoform 3: Cytoplasm: P10721
• Total number of polymer chains: 1
• Total formula weight: 36338.70

Authors

Zhou, T.,Zhu, X.,Dalgarno, D.C. (deposition date: 2014-07-11, release date: 2014-10-08, Last modification date: 2023-12-27)

Primary citation

Garner, A.P.,Gozgit, J.M.,Anjum, R.,Vodala, S.,Schrock, A.,Zhou, T.,Serrano, C.,Eilers, G.,Zhu, M.,Ketzer, J.,Wardwell, S.,Ning, Y.,Song, Y.,Kohlmann, A.,Wang, F.,Clackson, T.,Heinrich, M.C.,Fletcher, J.A.,Bauer, S.,Rivera, V.M.
Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients.
Clin.Cancer Res., 20:5745-5755, 2014

PubMed Abstract: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST.

PubMed: 25239608
DOI: 10.1158/1078-0432.CCR-14-1397

Experimental method

X-RAY DIFFRACTION (2 Å)