3QTI

c-Met Kinase in Complex with NVP-BVU972

3QTI の概要

• エントリーDOI: 10.2210/pdb3qti/pdb
• 分子名称: Hepatocyte growth factor receptor, 6-{[6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]methyl}quinoline, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: kinase, transerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P08581
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71651.79

構造登録者

Appleton, B.A. (登録日: 2011-02-22, 公開日: 2011-07-06, 最終更新日: 2024-02-21)

主引用文献

Tiedt, R.,Degenkolbe, E.,Furet, P.,Appleton, B.A.,Wagner, S.,Schoepfer, J.,Buck, E.,Ruddy, D.A.,Monahan, J.E.,Jones, M.D.,Blank, J.,Haasen, D.,Drueckes, P.,Wartmann, M.,McCarthy, C.,Sellers, W.R.,Hofmann, F.
A Drug Resistance Screen Using a Selective MET Inhibitor Reveals a Spectrum of Mutations That Partially Overlap with Activating Mutations Found in Cancer Patients.
Cancer Res., 71:5255-5264, 2011

PubMed Abstract: The emergence of drug resistance is a primary concern in any cancer treatment, including with targeted kinase inhibitors as exemplified by the appearance of Bcr-Abl point mutations in chronic myeloid leukemia (CML) patients treated with imatinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded mutation spectra that faithfully recapitulated clinical observations. To predict resistance mutations in the receptor tyrosine kinase MET that could emerge during inhibitor treatment in patients, we conducted a resistance screen in BaF3 TPR-MET cells using the novel selective MET inhibitor NVP-BVU972. The observed spectrum of mutations in resistant cells was dominated by substitutions of tyrosine 1230 but also included other missense mutations and partially overlapped with activating MET mutations that were previously described in cancer patients. Cocrystallization of the MET kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of NVP-BVU972, as previously reported for multiple other selective MET inhibitors. A second resistance screen in the same format with the MET inhibitor AMG 458 yielded a distinct spectrum of mutations rich in F1200 alterations, which is consistent with a different predicted binding mode. Our findings suggest that amino acid substitutions in the MET kinase domain of cancer patients need to be carefully monitored before and during treatment with MET inhibitors, as resistance may preexist or emerge. Compounds binding in the same manner as NVP-BVU972 might be particularly susceptible to the development of resistance through mutations in Y1230, a condition that may be addressed by MET inhibitors with alternative binding modes.

PubMed: 21697284
DOI: 10.1158/0008-5472.CAN-10-4433

実験手法

X-RAY DIFFRACTION (2 Å)